Serum levels of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) in the differential diagnosis of the syndromes of inappropriate secretion of TSH

Abstract

Background and objective: Serum TSH assay is a very sensitive and specific index of thyroid hormone (TH) action. Nevertheless, in particular clinical situations, such as those of inappropriate TSH secretion, the measurement of additional parameters evaluating peripheral TH action may be required in order to achieve a correct diagnosis and to assess the impact that thyroid hormone have on a given tissue. The availability of a specific RIA for serum carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) prompted us to study the usefulness of this specific marker of bone resorption in the differential diagnosis of thyroid disorders.

Design: Serum ICTP levels were measured in: (a) 10 patients with TSH-secreting pituitary adenoma (TSH-oma), (b) 40 with thyroid hormone resistance (RTH), as well as in (c) 28 patients with Graves' disease or toxic nodular goitre, (d) 31 with autoimmune primary hypothyroidism (PH) and in 8 of them during L-T4 replacement therapy, (e) 23 with central hypothyroidism (CH) during L-T4 therapy and 2 months after its withdrawal, and (f) 26 during TSH-suppressive treatment for goitre or non-metastatic differentiated thyroid cancer. Results were compared with those obtained in 2 groups of normal controls (Group A, n = 61, age range: 23-68 years; Group B, n = 32, age range: 6-15 years).

Methods: Serum TSH, free T4 (FT4) and free T3 (FT3) were measured by immunofluorometric assays. Serum ICTP was measured by a specific RIA with a sensitivity of 0.5 +/- 0.1 microgram/l, and intra- and interassay coefficients of variation lower than 6%.

Results: Mean values of serum ICTP levels in adult controls were 3.8 +/- 1.6 (+/-SD) microgram/l, while in pre- or peri-pubertal controls it was higher than in adults (14.4 +/- 3.1 micrograms/l). Patients with TSH-oma showed significantly increased ICTP levels (8.7 +/- 5.0 micrograms/l, P < 0.001 vs controls), in contrast to those with RTH (3.0 +/- 1.0 micrograms/l, P < 0.02 vs controls). In the differential diagnosis of inappropriate secretion of TSH, ICTP values above 5 micrograms/l strongly indicated the presence of a TSH-oma. Circulating ICTP concentrations were definitely high in thyrotoxic patients (9.4 +/- 4.7 micrograms/l, P < 0.001) and values overlapping the normal range were observed in 8 cases, thus giving to this test a sensitivity and specificity of 71% and 93%, respectively. In contrast, serum ICTP levels in both PH and CH untreated patients were in the normal range, although significantly lower than in controls (2.6 +/- 1.0 and 1.8 +/- 0.7 micrograms/l, P < 0.001). During replacement therapy, ICTP levels rose significantly in both hypothyroid groups (5.1 +/- 2.5 and 2.7 +/- 1.3 micrograms/l). In 2 CH patients, borderline high ICTP levels (7.0 and 7.1 micrograms/l), associated with FT3 concentrations in the upper limit of the normal range, suggested the presence of L-T4 overtreatment; L-T4 dose reduction was followed by the decrease of both indices in a more physiological range (ICTP: 4.2 and 4.7 micrograms/l; FT3: 8.5 and 6.0 pmol/l). In patients treated with TSH-suppressive therapy at the minimal effective dose, ICTP levels did not significantly differ from those observed in adult controls (4.3 +/- 2.0 micrograms/l). The overall correlations between serum ICTP and FT4 or FT3 levels were highly significant (P < 0.001).

Conclusions: The present data indicate that serum type I collagen (ICTP) concentrations are modulated by circulating thyroid hormone concentrations. ICTP measurement is particularly useful in the differential diagnosis of the syndromes of inappropriate TSH secretion, in estimating thyroid hormone impact on bone in primary hyperthyroid states, and its longitudinal evaluation may reveal L-T4 overtreatment in patients on substitutive or TSH-suppressive therapy.