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Serum thyroid stimulating hormone in assessment of severity of tissue hypothyroidism in patients with overt primary thyroid failure: cross sectional survey

Christian Meier, senior registrar in endocrinology, Peter Trittibach, clinical research fellow, Merih Guglielmetti, statistician, Jean-Jacques Staub, emeritus professor of endocrinology, Beat Müller, head of division. 

Division of Endocrinology, Department of Medicine, University Hospital, CH-4031 Basle, Switzerland

Correspondence to: C Meier cmeier{at}uhbs.ch

Primary hypothyroidism is a graded phenomenon with a wide spectrum of severity between subclinical hypothyroidism and overt hypothyroidism. Patients with biochemically severe hypothyroidism may present with only mild clinical manifestations, whereas some patients with moderate changes in thyroid hormones may present with severe signs of tissue hypothyroidism.¹ The measurement of pituitary thyroid stimulating hormone (TSH) is the most sensitive test for early diagnosis of primary hypothyroidism. The magnitude of elevation of TSH is commonly believed to correspond to the severity of tissue hypothyroidism. We aimed to evaluate the value of measuring serum TSH in assessing the severity of tissue hypothyroidism in patients with overt hypothyroidism.

	Methods and results

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We recruited 49 patients with overt hypothyroidism (TSH >20 mU/l, free thyroxine <8.0 pmol/l; mean age 56.6 (SD 12.1) years) from a cohort of female patients followed prospectively in the thyroid research unit of the endocrine outpatient clinic. The patients had underlying thyroid disorders of chronic autoimmune thyroiditis (n=30), treated Graves' hyperthyroidism (radioiodine or surgery; 16), thyroidectomy for simple goitre (2), and treated toxic adenoma (1). We excluded non-thyroidal illnesses in all women. In addition to measuring TSH and peripheral thyroid hormones (free thyroxine and triiodothyronine) we assessed clinical and metabolic markers of hypothyroidism (clinical score, ankle reflex time, creatine kinase, total cholesterol) to evaluate thyroid hormone action at the tissue level.^1-3 To estimate the association between thyroid hormones and markers of tissue hypothyroidism we correlated TSH and thyroid hormone concentrations with the different tissue parameters. The ethics committee for human studies approved the study.

The table summarises the correlation analyses of thyroid hormone concentrations with different markers of tissue hypothyroidism. In contrast to the good correlations with both circulating thyroid hormones, we found no correlation or only weak correlations with serum TSH.

We then used the Mann-Whitney U test to analyse patients' data in relation to the severity of tissue hypothyroidism as assessed by ankle reflex time (patients with moderate prolongation (410-550 ms; n=15) compared with patients with severe prolongation (>550 ms; 15)). Free thyroxine concentrations declined significantly between these groups (from median 5.5 (range 1.9-7.8) pmol/l to 2.5 (1.8-3.5) pmol/l; P=0.001), as did triiodothyronine (1.0 (0.7-1.6) nmol/l to 0.8 (0.2-1.1) nmol/l; P=0.002). We also found an impairment of the clinical score (from 5 (3-11) points to 8.5 (6-11) points; P=0.005), creatine kinase (144.0 (62.0-362.0) U/l to 566.0 (229.0-2170) U/l; P<0.001), and total cholesterol (7.63 (5.7-11.2) mmol/l to 9.4 (7.8-14.2) mmol/l; P=0.003). In contrast, we found no difference in TSH concentrations between the groups (from 42.0 (26.1-137.0) mU/l to 53.8 (23.6-95.3) mU/l; P=0.44).

	Comment

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TSH is a poor measure for estimating the clinical and metabolic severity of primary overt thyroid failure. This is in sharp contrast to the high diagnostic accuracy of TSH measurement for early diagnosis of hypothyroidism.

We found no correlations between the different parameters of target tissues and serum TSH. Our findings are in accordance with a cross sectional study showing only a modest correlation between TSH and the percentage of positive hypothyroid symptoms⁴ and data showing discordant responses between the pituitary and peripheral target tissues in patients treated with L-triiodothyronine.⁵ We assume that secretion of TSH is driven by maximal stimulation, with no further increase occurring with greater severity of hypothyroidism. Therefore, the biological effects of thyroid hormones at the peripheral tissuesand not TSH concentrationsreflect the clinical severity of hypothyroidism. A judicious initiation of thyroxine treatment should be guided by clinical and metabolic presentation and thyroid hormone concentrations (free thyroxine) and not by serum TSH concentrations.

	Acknowledgments

We thank the laboratory staff of the division of endocrinology (Maya Kunz, Sylvia Alscher, Ursula Schild) for performing the biochemical and technical analyses.

Contributors: CM, J-JS, and BM were involved in the conceptual design, interpretation of data, critical revision of the paper, and approval of the final version. CM, PT, and MG were involved in data collection and analysis. BM and J-JS are the guarantors.

	Footnotes

Editorial by Toft and Beckett

Funding: Swiss Research Foundation (grants 32.27866.89, 32.37792.93, and 32.37792.98); unconditional research grants from Sandoz Research and Roche Research Foundations (to J-JS), the Sonderprogramm zur Förderung des akademischen Nachwuchses der Universität Basel, and the Nora van Meeuwen-Häfliger Foundation (to BM).

Competing interests: None declared.

	References

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1.	Zulewski H, Muller B, Exer P, Miserez AR, Staub JJ. Estimation of tissue hypothyroidism by a new clinical score: evaluation of patients with various grades of hypothyroidism and controls. J Clin Endocrinol Metab 1997; 82: 771-776[Abstract/Free Full Text].
2.	Staub JJ, Althaus BU, Engler H, Ryff AS, Trabucco P, Marquardt K, et al. Spectrum of subclinical and overt hypothyroidism: effect on thyrotropin, prolactin, and thyroid reserve, and metabolic impact on peripheral target tissues. Am J Med 1992; 92: 631-642[CrossRef][Web of Science][Medline].
3.	Franklyn JA, Daykin J, Betteridge J, Hughes EA, Holder R, Jones SR, et al. Thyroxine replacement therapy and circulating lipid concentrations. Clin Endocrinol (Oxf) 1993; 38: 453-459[Medline].
4.	Canaris GJ, Steiner JF, Ridgway EC. Do traditional symptoms of hypothyroidism correlate with biochemical disease? J Gen Intern Med 1997; 12: 544-550[CrossRef][Web of Science][Medline].
5.	Ridgway EC, Cooper DS, Walker H, Daniels GH, Chin WW, Myers G, et al. Therapy of primary hypothyroidism with L-triiodothyronine: discordant cardiac and pituitary responses. Clin Endocrinol (Oxf) 1980; 13: 479-488[Medline].

(Accepted 2 September 2002)