Internal Medicine Journal 39 (2009) 117120

B R IE F C O M M U N IC AT I O N

Cardiac troponin T is not increased in patients with hypothyroidism

R. Ness-Abramof,1 D. A. Nabriski,1 M. S. Shapiro,1 L. Tripto-Shkolnik,2 B. Katz,3 E. Weiss4 and L. Shenkman5
1

Endocrine Unit, 2Department of Medicine A, 3Clinical Chemistry Laboratory, 4Endocrine Laboratory and 5Department of Medicine C, Sapir Medical Center, Kfar Saba and the Sackler Faculty of Medicine, Tel Aviv University, Meir Hospital, Tel Aviv, Israel

Key words troponin T, creatine phosphokinase, creatine kinase-MB, thyroid, hypothyroidism. Correspondence Rosane A. Ness, Endocrine Unit, Sapir Medical Center, Tchernikovsky 53, Kfar Saba, Israel. Email: rosane-abramof.ness@clalit.org.il Received 14 December 2007; accepted 3 April 2008. doi:10.1111/j.1445-5994.2008.01856.x

Abstract
Patients with hypothyroidism often have increased creatine kinase (CK) levels. It is possible that there is increased production of CK, but other mechanisms, such as an increased cell membrane permeability or decreased enzyme clearance were also proposed. Recently, troponins T and I have been extensively studied because of their cardiac specicity. Cardiac troponins are sensitive and specic markers of cardiac injury. The objective of the study was to measure cardiac troponin T (cTnT) levels in patients with hypothyroidism. Twenty-ve patients with primary hypothyroidism were evaluated (thyroid-stimulating hormone (TSH) >30 mU/L and low FT4). In all patients thyrotropin (TSH), free thyroxine (FT4), CK, CK-MB and cTnT were measured.There were 3 men and 22 women with a mean age of 47.5 12.4 years. TSH levels ranged from 31 to 75 mIU/L and mean FT4 levels were 4.5 1.9 pmol/L. CK was normal in 11 patients and increased in 14. CK levels ranged between 86 and 1221 U/L (normal levels <170 in women, <195 in men) with a mean of 322 U/L 279. CK-MB was increased in 4 patients (16%) and normal in 21. All 25 patients had normal cTnT levels, < 0.01 ng/mL (normal levels 00.1 lg/L). Increase in CK and its MB fraction are common in patients with hypothyroidism but cTnT levels are not, even in patients with increased CK-MB. Therefore, cTnT is a reliable marker of cardiac injury even in the hypothyroid patient.

It is well known that hypothyroidism may be associated with high levels of creatine kinase (CK). Increase in CK in hypothyroidism was rst described by Graig and Ross in 1963, when they reported high CK levels in hypothyroid patients and observed that values normalized after thyroid hormone replacement.1 Since then, others have made similar observations.2,3 Several reasons have been proposed for the increased CK activity in hypothyroidism, including increased isoenzyme production, increased permeability of cell membrane or decreased clearance of the enzyme.4 It has been generally presumed that only the MM isoenzyme is increased, but the CK-MB isoenzyme

Funding: None Potential conicts of interests: None

2009 The Authors Journal compilation 2009 Royal Australasian College of Physicians

may also be increased in hypothyroid patients without evidence of myocardial infarction or myocarditis.5 Troponins are proteins found in striated muscle cells. Cardiac troponins are currently used as biochemical markers of myocardial necrosis because they are sensitive and specic markers of myocardial damage. Serum concentration of cardiac troponins increase within a few hours of cardiac damage and remain increased for a few days.6 Presently, the diagnosis of myocardial infarction increasingly is based on increased cardiac troponin concentration.7 Cardiac troponin T (cTnT) is a component of the troponin complex, and is the most widely used troponin for the diagnosis of myocardial damage.8 In spite of its specicity for myocardial damage, cTnT may be increased in patients without coronary syndrome, as for instance in patients with severe renal dysfunction, myocarditis,
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pulmonary embolism, acute heart failure, rhabdomyolosis and septic shock.912 Patients with hypothyroidism may complain of chest pain with non-specic electrocardiographic changes and increased CK-MB levels, a clinical picture suggestive of myocardial infarction.1214 To our knowledge, cTnT has not been measured prospectively in patients with hypothyroidism and therefore we decided to conduct this study. We conducted a prospective study of hypothyroid patients referred to the endocrine outpatient clinic (Meir Medical Center, Kfar Saba, Israel) and patients that underwent thyroidectomy for thyroid cancer and were admitted for radioactive iodine therapy (on thyroid hormone withdrawal for at least 4 weeks). Inclusion criteria included a thyroid-stimulating hormone level (TSH) > 30 mIU/L and a low FT4 (<10.3 pmol/L). Patients with chronic renal failure and patients evaluated for cardiac symptoms were not included in the study. The following laboratory tests were carried out in all patients: thyrotropin (TSH), free thyroxine (FT4), CK, CKMB, liver function tests, total cholesterol, creatinine, urea and troponin T. TSH and FT4 were measured by Immulite 2000 (DPC, Los Angeles, CA, USA), normal range: TSH 0.234 mIU/L, FT4 10.325 pmol/L. CK-MB activity was measured by Roche UV assay based on immunological inhibition of CK-M by a Hitachi 917 analyser (Roche, Manheim, Germany). The normal range is < 25 U/L in accordance with the manufacturers instructions and <5% of the total CK activity; analytical sensitivity 1U/L, CV within run 1.5%, CV between day 2.8%. Total CK activity was measured by the same system with a Roche CK-NAC liquid UV assay. Normal range for men 15195 U/L and women 15170 U/L; analytical sensitivity 3 U/L, CV within run 1.1%, CV between day 1.9%. The method did not include an adenylate kinase (AK) blank, but to reduce AK interference to a minimum, AMP and Ap5A mixture was added to the reagent causing 9597% inhibition of the AK. Cardiac troponin T was measured by Elecsys Troponin T Stat 3rd generation (Roche Diagnostics, IN, USA). The analytical sensitivity was 0.01 lg/L, the normal range being 00.1 lg/L and the measuring range 0.0125 lg/L. Analytical specicity for the monoclonal antibodies used are: h-skeletal muscle troponin T, 0.001%, h-cardiac troponin I, 0.002%, h-skeletal muscle tropomyosin, 0.001%, h-cardiac tropomyosin, 0.1% and h-cardiac myosin light chain 1, 0.003%. The study was approved by a local review board and all patients signed a written informed consent. Statistical analysis was carried out with the use of SPSS 12 statistical software. Data were expressed as mean SD.

Comparison between groups was assessed by the Mann Whitney test. Fishers exact test and Pearsons v2-test were used when appropriate. P < 0.05 was considered statistically signicant. Twenty-ve patients with hypothyroidism were recruited. The cause of hypothyroidism was thyroidectomy and thyroxine withdrawal before 131I therapy in 24 and 131I therapy for Graves disease in one. There were 3 men and 22 women with a mean age of 47.5 12.4 years. TSH values ranged from 31 to 75 mIU/L (normal 0.3 4 mU/L). Mean FT4 was 4.5 pmol/L 1.9, ranging from 0 to 7.7 pmol/L (normal 10.325 pmol/L). Mean CK was 322 U/L 279, ranging from 86 to 1220 U/L (normal levels men 15195 U/L, women 15 170 U/L)(Fig. 1). Mean CK-MB was in units 15.6 8.5 U/L, ranging from 7 to 46 U/L (normal levels 020 U/L) and CK-MB% was 6.5% 3.9, ranging from 2.6 to 17.6% (normal levels 05%). Eleven patients (44%) had normal total CK (mean standard deviation (SD) 132 U/L 30) whereas 14 (56%) had increased CK levels (mean SD 472 U/L 298). Ten patients had increased CK but normal CK-MB whereas four patients had increased levels of CK and CK-MB units. CK-MB units were normal in 21 patients and increased in 4, whereas CK-MB% was normal in 12 patients (48%) and increased in 13 (52%). In one patient both CK-MB units and CK-MB% were increased. CK was increased in all 3 men and in 11 women (50%) but the difference between genders was not statistically signicant (P = 0.158). Mean CK was 705 239 in men and 270 244 in women (P = 0.015). CK-MB units were normal in 1 man (33.3%) and increased in 2 (66.7%) while it was normal in 20 women (91%) and increased in 2 (9%)(P = 0.029). Cardiac troponin T (cTnT) was <0.01 lg/L (normal limit 00.1 lg/L) in all 25 patients (Table 1). Now cardiac troponins are used widely for the diagnosis of myocardial injury and for the management of acute coronary syndromes (ACS). The Joint European Society of Cardiology/American College of Cardiology committee proposed that a diagnosis of myocardial infarction should be based on the increase in cardiospecic biomarkers (troponin T and troponin I).7 Although troponin T and I are expressed in cardiac and skeletal muscles, its amino acid sequences differ, allowing for monoclonal antibodies to be formed against the specic cardiac troponins.15 Both are sensitive and specic markers of myocardial damage and may serve as prognostic indicators of future cardiac events. Cardiac troponin T is widely used as the biomarker of choice for the detection of cardiac injury because of its better standardization.10 Patients with hypothyroidism may present with signs and symptoms suggestive of myocardial infarction, with
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Table 1 Characteristics and laboratory results of 25 hypothyroid patients Parameter Age (years) Sex (male/female) TSH (mIU/L) (nl 0.234) FT4 (pmol/L) (nl 10.325) CK (U/L) (nl men <195, women <170) CK-MB (U/L) (nl <20 Creatinine (lmol/L) (nl men 62124, women 44106) Cholesterol (mmol/L) (nl 3.65.2) cTnT (lg/L) (nl 001 lg/L) 47.5 12.5 3/22 3175 0.36 0.15 322 279 15.6 8.5 97.2 8.8 6.9 1.3 <0.01

CK, creatine kinase; cTnT, cardiac troponin T; FT4, free thyroxine; nl, normal levels; TSH, thyroid-stimulating hormone.

but possibly of skeletal muscle origin. Furthermore, we nd that cTnT is not spuriously increased in patients with hypothyroidism, as has been previously implicated10 and it is a reliable tool for assessing ACS in this patient group. Although most of our patients had hypothyroidism for a short period of time (45 weeks), this period was sufcient to cause signicant biological changes such as an increase in CK and cholesterol levels, making our results relevant. Hypothyroidism causes mainly skeletal muscle myopathy with the concomitant increase in CK and its MB isoenzyme. Cardiac troponin T is not increased in patients with hypothyroidism without cardiac symptoms. If cTnT is increased, it should be considered a marker of cardiac injury and not be attributed to the concomitant hypothyroidism.

increased CK and electrocardiographic abnormalities, or occasionally a hypothyroid patient may have concomitant heart disease making the diagnosis of ACS imperative for the proper management of these patients.12,13 Recently two case reports were published.12,14 Gunduz et al. described a hypothyroid patient that presented with chest pain, electrocardiographic changes, and increased cardiac enzymes, including troponin I with a normal coronary angiography. In this case the increase in troponin was attributed to the hypothyroidism. Buschmann et al., reported a patient with cardiac symptoms, electrocardiographic changes, increased cardiac enzymes, including cTnT and cTnI and normal cardiac angiogram, but in this case, magnetic resonance imaging showed a small area of diffuse myocardial damage. Although the myocardial damage was possibly not ischaemic in origin, troponin levels were not spuriously increased. It is known that patients with hypothyroidism may have increased levels of CK and of its MB fraction.16 In our study 56% of the patients had increased CK levels with 16% also having increased CK-MB, a nding similar to previously published reports. Men had higher CK and CK-MB levels compared with women. Whether the source of the MB was skeletal muscle or cardiac has not been properly studied. Cohen et al. published a retrospective laboratory-based study including 52 patients with TSH >25 mIU/L with FT4 levels ranging from low to normal. They found that CK was increased in 65% of patients and CK-MB isoenzyme was so in 13.5% of patients. In all patients cardiac troponin I was within reference range (<0.4 lg/L).17 Our work is the rst prospective study in which cTnT was measured in patients with hypothyroidism. Our cohort included patients with increased CK, including increased CK-MB. In all patients cTnT was undetectable, proving that the increased CK-MB is not of cardiac origin,
2009 The Authors Journal compilation 2009 Royal Australasian College of Physicians

Acknowledgement
The authors are thankful to Michal Ness for her assistance and to Mila Grankin for the statistics; Statistics Unit, Meir Hospital, Tel Aviv, Israel.

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