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00019616-200405000-00011ReviewThe EndocrinologistThe Endocrinologist© 2004 Lippincott Williams & Wilkins, Inc.14May 2004 p 161-166Effect of l-Thyroxine Replacement Therapy on Surrogate Markers of Skeletal and Cardiac Function in Subclinical HypothyroidismCME Review Article #19Christ-Crain, Mirjam MD*; Meier, Christian MD†; Huber, Peter R. PhD‡; Staub, Jean-Jacques MD§; Müller, Beat MD¶*Fellow, †Senior Registrar, §Emeritus Professor, ¶Associate Professor, Division of Endocrinology, Diabetes, and Clinical Nutrition, Department of Internal Medicine and ‡Full Professor, Department of Central Laboratories, University Hospitals, Basel, Switzerland.Supported by grants from the Swiss National Science Foundation (32.27866.89, 32.37792.93, and 32.37792.98) and unconditional research grants from Henning Berlin, Novartis, Roche Research, Nora van Meeuwen-Häfliger, and Krokus Foundations and the “Sonderprogramm zur Förderung des akademischen Nachwuchses der Universität Basel” (to BM).The authors have disclosed that they have no significant relationships with or financial interests in any commercial company that pertains to this educational activity.Reprints: Mirjam Christ-Crain, MD, Division of Endocrinology, Department of Internal Medicine, University Hospitals, Petersgraben 4, CH-4031 Basel, Switzerland. E-mail: [email protected] Editor’s Note: This article is the 19th of 36 that will be published in 2004 for which a total of up to 36 Category 1 CME credits can be earned. Instructions for how credits can be earned precede the CME Examination at the back of this issue.AbstractOvertly impaired thyroid function affects skeletal and cardiac muscle function, reflected in increased circulating skeletal muscle enzyme levels (ie, creatine kinase [CK] and myoglobin [Mb]), prolonged ankle reflex time (ART), and altered systolic time intervals (STI). The response of these markers of muscular function to l-T4 replacement therapy in patients with subclinical hypothyroidism was evaluated in a prospective, double-blind study. Sixty-six women with subclinical hypothyroidism (thyroid-stimulating hormone [TSH] 12.9 ± 8.2 mU/L) were randomly assigned to receive l-thyroxine or placebo for 48 weeks. Sixty-three of the 66 women completed the study. Mb, CK, ART, and STI were measured at baseline and 48 weeks after l-thyroxine or placebo treatment, respectively. In patients with markedly elevated TSH levels at baseline (>12 mU/L), the ART decreased significantly after 48 weeks of l-thyroxine treatment (P = 0.01). There was no treatment effect on circulating CK or Mb levels. The STI were not altered in subclinical hypothyroidism and consequently remained unchanged by l-thyroxine treatment. ART is significantly reduced after l-T4 replacement therapy in patients with markedly elevated TSH levels at baseline. CK and Mb, representing surrogate markers of muscle function, as well as systolic cardiomuscular function, assessed by measurement of resting left ventricular systolic function, are not affected in subclinical hypothyroidism. This suggests a mildly affected, yet compensated neuromuscular dysfunction. Of various potential surrogate markers of muscular function, ART seems to reflect best the subtle changes of mild thyroid failure.Learning ObjectivesList the baseline characteristics of subclinical hypothyroidism (SCH) in this study population of 62 women.Describe the effects of l-thyroxine treatment on thyroid hormone levels, skeletal muscle function, and systolic cardiac muscle function in women with SCH.Explain the implications of these findings for the nature of hypothyroidism, and for the preferred means of following the response to treatment in women with SCH.Thyroid hormones affect several peripheral target organs, including heart and skeletal muscle.1 The association of myopathy with both marked hyper- and hypothyroidism is well established.2–5 In overt hypothyroidism (OH), elevated concentrations of muscle enzymes, especially creatine kinase (CK) and myoglobin (Mb) levels, have been reported, indicating skeletal muscle dysfunction.3,6 Both the lowered metabolic clearance and an increased leakage by the skeletal muscle tissues could be responsible for the observed effects.7A prolonged ankle reflex time (ART) is a recognized characteristic of hypothyroidism.8–11 OH is also associated with impaired myocardial contractility and ventricular systolic and diastolic function, indicating cardiac muscle function abnormality.12,13 To assess systolic myocardial function, systolic time intervals (STI), a noninvasive technique, can be calculated with significant changes found in patients with OH.14As a result of the widespread use of TSH measurements, subclinical hypothyroidism (SCH) has been detected with increasing frequency in the past years. SCH, characterized by the finding of elevated TSH levels in the presence of normal circulating thyroid hormones,15 is causing major controversies concerning management and treatment. In SCH, moderately increased levels of CK, Mb, and ART have been reported11,16 as well as an impaired myocardial contractility,17 but unchanged STI.11,18 Some clinical trials showed a significant treatment effect of T4 replacement therapy both on ART18 and STI.13,19,20 Although some studies were double-blind and placebo-controlled, others were uncontrolled in which patients could have received excess doses of thyroid hormones. An unchanged CK level during l-T4 replacement therapy has been shown in one study,20 whereas the effect of l-thyroxine treatment on Mb in SCH has not yet been investigated. We describe various parameters of muscular function in SCH as well as the effect of a well-controlled, TSH-guided l-thyroxine treatment analyzing data from a double-blind study.21MATERIALS AND METHODSStudy SubjectsThe present analysis was part of a prospective, double-blind, placebo-controlled study whose design and patient characteristics have been described previously.21 Briefly, 66 women with SCH were enrolled in the study. All patients were examined and followed up in the Thyroid Research Unit of the Division of Endocrinology, Department of Medicine, University Hospitals Basel, Switzerland. Patients between 18 and 75 years of age with TSH levels more than 5.0 mIU/L on 2 consecutive blood tests at least 3 months apart, exaggerated TSH response after oral TRH stimulation, free T4 concentration within the normal range, and good general health were included. After an overnight fast, all the women underwent full medical assessment and laboratory examinations to rule out nonthyroidal illnesses. Exclusion criteria were coronary heart disease, pituitary/hypothalamic disorders as well as thyroid hormone medication up to 3 months before enrollment. A total of 63 women (mean age, 58.5 ± 1.3 years) completed the study according to the study protocol, with no serious adverse events reported. No patient had a concomitant use of drugs known to affect neuromuscular function. Specifically, the following over-the-counter and prescribed drugs were taken: nonsteroidal antiinflammatory drugs (T4 group: 5/31, placebo group: 3/32), benzodiazepines (T4 group: 4/31, placebo: 3/32), barbiturates (T4 group: 0/31, placebo group: 1/32), diuretics (T4 group: 1/31, placebo: 1/32), β-blockers (T4 group: 3/31, placebo: 3/32), bisphosphonates (T4 group: 0/31, placebo: 2/32), magnesium (T4 group: 2/31, placebo: 0/32), haloperidol (T4-group: 1/31, placebo: 0/32), nitroglycerin (T4-group: 1/31, placebo: 0/32), calcium antagonists (T4 group: 1/31, placebo: 0/32), and angiotensin-converting enzyme inhibitors (T4 group: 2/31, placebo: 1/32). The intake of none of these drugs was different in the T4-treated group as compared with the placebo group.The study was terminated early in 3 participants as a result of previously unknown serious medical comorbidities and rapid progression to clinically overt hypothyroidism, respectively. In addition, because of lacking muscle test values, 1 patient in the placebo group was excluded from analysis. The underlying thyroid disorders leading to SCH consisted of autoimmune thyroiditis (n = 32), Graves’ disease (n = 20; treated with radioiodine, surgery, or carbimazole), toxic multinodular goiter (n = 1, treated with radioiodine), surgically resected goiter (n = 6), and idiopathic SCH (n = 3). The frequencies of underlying thyroid disorders were equally distributed in the l-thyroxine and placebo groups.Study DesignWe used a prospective, double blind, placebo-controlled trial design, as previously described.21 Eligible patients were sequentially assigned either to the l-T4 treatment group (n = 31) or to the placebo group (n = 32) according to a predefined randomization list. The study duration for each patient was 50 weeks, including a 2-week run-in phase before starting treatment. During the first 24 weeks, the l-T4 dose was adapted continuously every 6 weeks to achieve an optimal physiological hormone replacement with euthyroid basal TSH levels (ie, basal TSH concentration within the reference range [0.3–4.0 mIU/L]). The dosage was controlled every 6 weeks to ascertain an optimal replacement regimen. The local Ethics Committee for Human Studies approved the study. All patients gave their written informed consent to participate in the trial.Hormone Measurements and Tests of Peripheral Hormone ActionSerum samples were collected in the fasting state, immediately put on ice and processed within 30 minutes. Thereafter, they were kept frozen at −70°C. Hormone measurements were assessed at baseline and at the end of the study after 48 weeks.The serum TSH concentration (reference range, 0.3–0.4 mU/L) was measured with an immunometric assay (Delfia, Wallac, Inc., Turku, Finland). Free T4 (8.0–23.0 pmol/L) and total T3 (1.2–3.1 nmol/L) were determined by microparticle enzyme immunoassays (Imx; Abbott Laboratories, Inc., Chicago, IL). Mb was measured by microparticle–enzymatic immunoassay (MEIA) (Axsym; Abbott AG, Baar, Switzerland; reference range, <116 μg/L). CK was measured by enzymatic assay (Roche Diagnostics, d-Mannheim, Germany; reference range, 26–140 U/L). The ankle reflex time was measured by photomotography with an achillometer (Polymed, Glattbrugg, Switzerland; reference range, 290–410 ms); 6 tracings (3 on each ankle) were recorded for each woman. The ART was the mean of the 6 readings, as previously described.10,11 STIs were calculated after simultaneous recording of electrocardiogram, phonocardiogram, and carotid pulse tracing. The left ventricular ejection time (LVET; reference range for women, 418 ± 11 ms) was measured from the carotid upstroke to the incisure. We measured the electromechanical systole (QS2-interval, reference range for women, 549 ± 14 ms) from the earliest QRS activity to the first deviation from the baseline of the hearing-like phonocardiographic recording of the second heart sound, corresponding to the aortic valve closure. The preejection time (PEP; reference range for women, 133 ± 10 ms) was calculated by substraction of LVET from QS2. In all the patients, the ratio LVET/PEP was calculated. The values for LVET and PEP were corrected for heart rate by the Weissler equations.22Statistical AnalysesAll data are expressed as mean ± standard deviation (sd) in text and tables and as mean ± standard error of the mean (sem) in figures. Mann-Whitney U test was used to show differences among the groups. Treatment effects in the l-thyroxine or placebo group were analyzed by Wilcoxon signed rank test. P values <0.05 were considered statistically significant. Data were analyzed using Statistica for Windows (version 5.0; StatSoft, Inc., Tulsa, OK).RESULTSBaseline CharacteristicsAt baseline, the 2 groups of women with SCH (l-thyroxine, n = 31; placebo, n = 31) were similar with respect to age, body mass index, thyroid hormone concentrations, and muscle function tests, namely Mb and CK levels, ART and STI values. In both groups, basal TSH levels were mildly to markedly elevated (range, 5.0–50 mU/L) with an exaggerated TSH response of more than 35 mIU/L after oral TRH administration. Peripheral thyroid hormone concentrations (fT4 and T3) were within the lower reference range (Table 1).JOURNAL/endst/04.03/00019616-200405000-00011/table1-11/v/2021-02-17T201731Z/r/image-tiff Baseline Characteristics of PatientsEffect of Treatment on Thyroid Hormone ConcentrationsIn the l-thyroxine treatment group, the dose was adapted in 6-week intervals to decrease the TSH concentration to the euthyroid reference range (mean daily dose, 85.8 ± 24.3 μg; range, 50–125 μg). In all patients, TSH concentrations were within the reference range at least for the last 24 weeks. Mean serum TSH level at the end of the study was 3.1 ± 1.6 mIU/L. No patient had a blunted or absent TSH response to thyrotropin-releasing hormone, thereby excluding overtreatment. Peripheral thyroid hormone concentrations (fT4 and T3) remained within the reference range. As expected, no change in any variable of thyroid function could be seen in patients with placebo.Effect of Treatment on Skeletal Muscle FunctionAt baseline, circulating muscle enzyme concentrations and ART values were within the reference range (Table 1). After 48 weeks overall, there was no significant treatment effect either for Mb and CK levels or for ART in both treatment groups. However, in the subgroup of patients with markedly elevated TSH concentrations (TSH ≥12 mU/L, n = 13), we found a significant decrease of ART with l-thyroxine therapy (at baseline: 385.4 ± 48.5 ms, after 48 weeks of treatment: 361.0 ± 36.9 ms; P = 0.02, Fig. 1). Levels of CK decreased from 85.1 ± 30.2 U/L to 73.5 ± 20.8 U/L (P = 0.06). There was no T4-treatment effect on Mb levels (at baseline: 43.0 ± 15.4, after 48 weeks of treatment: 40.5 ± 13.5 μg/L; P = not significant) (Table 2). In placebo-treated patients, no significant changes of these parameters could be observed, except for a significant change in Mb levels in patients with TSH <12 mU/L at baseline.JOURNAL/endst/04.03/00019616-200405000-00011/figure1-11/v/2021-02-17T201731Z/r/image-tiff Ankle reflex time in patients with pretreatment thyroid-stimulating hormone levels below 12 mU/L (left side) and above 12 mU/L (right side) at baseline and after 48 weeks of l-T4 treatment. Diamonds represent means, boxes standard error of mean (sem), and whiskers 1.96. sem of the combined data.JOURNAL/endst/04.03/00019616-200405000-00011/table2-11/v/2021-02-17T201731Z/r/image-tiff Parameters Before and 48 Weeks After Treatment With l-Thyroxine or PlaceboEffect of Treatment on Systolic Cardiac Muscle FunctionIn all women, STI were measured at baseline and after 48 weeks of l-thyroxine and placebo treatment. Levels at baseline were within the reference range (Table 1). After 48 weeks of l-thyroxine therapy, there was no significant treatment effect on heart rate (HR), PEP, LVET, QS2, or the PEP/ LVET ratio. Equally, there was no significant treatment effect in the subgroup of patients with markedly elevated TSH concentrations at baseline (Table 2). In the placebo-treated group, no significant treatment effects could be observed.DISCUSSIONThyroid hormone replacement ameliorates the skeletal muscle dysfunction with significant decrease of ankle reflex time, which seems to be a sensitive marker of skeletal muscle dysfunction in SCH. In contrast, the muscle enzymes creatine kinase and myoglobin are not able to detect mild forms of thyroid dysfunction at the muscle tissue level. Furthermore, cardiomuscular function is not affected in SCH.In overt thyroid dysfunction, elevated CK and Mb levels and a prolonged ART have been shown with normalization after l-thyroxine treatment.3,6,23 In SCH, a mild elevation of Mb and the ART only in patients with markedly elevated TSH levels has been reported,11,16,18 indicating that muscle function is only affected in patients with marked SCH or in overt disease. Treatment effects on various markers of muscle function showed conflicting results.18,20Our results demonstrate values in SCH within the normal reference range for all measured skeletal muscle markers. However, normal reference ranges are a measure of interindividual variance and the “normal range” for a specific individual is much less wide. Accordingly, individual changes observed in this double-blind study can be relevant for an affected patient, despite being within the so-called “normal range.” ART is an integral measure of neuromuscular function. It has been well validated as a sensitive marker to reflect a lack of thyroidal hormone at the peripheral target tissue level.12 We observed a significant reduction of ART on restoration of euthyroidism in the subgroup of patients with markedly elevated TSH levels >12 mU/L at baseline. This supports the concept that hypothyroidism is a graded phenomenon, in which impending skeletal muscle dysfunction becomes apparent only in patients with markedly elevated TSH levels. For these subtle changes, ART is the most sensitive surrogate marker. In contrast, the muscle enzymes CK and Mb are not able to detect mild forms of thyroid dysfunction at the muscle tissue level and should therefore not be assessed in the evaluation of patients with SCH according to our results. We observed a significant increase of Mb levels in the placebo group with TSH levels below 12 mIU/L. However, based on the identical thyroid hormone levels before and after therapy, we believe that this is a statistical chance finding.Diastolic, rather than systolic, cardiac function seems to be mostly impaired by thyroid hormone deprivation.24–27 STI, which mirrors systolic myocardial function, was found to be within the upper normal range at baseline,11,18,28 improving after l-thyroxine therapy.13,18,19,20 Thereby, improvement was primarily seen in the patients with elevated baseline values and if excess doses of thyroid hormone were applied resulting in subclinical hyperthyroidism. To the best of our knowledge, our study is the only study that combines a double-blind design with randomization by matched pairs (either l-thyroxine or placebo group) and TSH-guided dose adaptations to guarantee physiological thyroid hormone replacement throughout the entire trial period. Our findings show STI within the normal reference range without l-thyroxine treatment effect, and suggest that the myocardial contractility as well as the resting systolic ventricular function is not affected in SCH. Thus, unlike the skeletal muscle system, the heart seems to be able to compensate in mild tissue hypothyroidism. Alternatively, ART could be more discriminatory and sensitive than STI in reflecting peripheral neuromuscular thyroid hormone action.This study has some limitations. This analysis was part of a prospective, controlled trial on l-T4 therapy effects on serum cholesterol and clinical outcome.21 Post-hoc analyses have potential limitations; hence, the data are primarily a physiopathologically interesting observation. In addition, our results are of interest, because published data on muscle function in SCH and the effect of l-T4 treatment are scarce.Based on the NHANES III, a lower normal range for serum TSH of 0.4–2.0 mIU/L has been suggested.29 The thyrotropin level at the end of our study was still in the upper normal reference range in the l-T4 group, which could indicate that some patients were treated with an inappropriately low dose of l-T4, resulting in a persistence of SCH. Hence, a more aggressive T4 substitution therapy could have resulted in more pronounced effects on heart function and circulating levels of muscle enzymes.In conclusion, surrogate markers of muscle function are in the normal reference range in SCH with a significant reduction of the ART after l-T4 replacement therapy in patients with markedly elevated TSH levels at baseline. This suggests an already affected yet compensated neuromuscular dysfunction. The ART can be used as follow-up measurement if T4 treatment is started. Based on our data, systolic cardiac muscle system, as assessed by measuring the resting left ventricular systolic function, is functionally not affected in SCH.ACKNOWLEDGMENTSThe authors thank S. Alscher and M. Kunz for their excellent technical assistance and M. Guglielmetti for her statistical advice.REFERENCES1.Ross DS. Subclinical Hypothyroidism. In: Braverman LE, Utiger RU, eds. Werner and Ingbar’s the Thyroid: A Fundamental and Clinical Text. 8th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2000: 1001–1006.[Context Link]2.Ramsay ID. Muscle dysfunction in hyperthyroidism. Lancet. 1966;2:931–934.[Context Link][CrossRef][Medline Link]3.Kasai K. Serum myoglobin level in altered thyroid states. J Clin Endocrinol Metab. 1979;48:1–4.[Context Link][CrossRef][Medline Link]4.Docherty I, Harrop JS, Hine KR, et al. 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