Normal Serum TSH Concentrations Research Articles

Use of thyroid hormones in hypothyroid and euthyroid patients: a THESIS* questionnaire survey of Polish physicians. *THESIS: Treatment of hypothyroidism in Europe by specialists: an international survey.

Over the past several years new evidence on the management of hypothyroidism has emerged, which has influenced recommendations from professional bodies. The presentation of hypothyroid patients has also changed, and new cases are increasingly diagnosed by indiscriminate screening, often identifying cases with minor biochemical disturbances. Little is known about the physician responses and attitudes to this changing landscape. THESIS (Treatment of Hypothyroidism in Europe by Specialists: an International Survey) is a large-scale survey of European physicians who treat patients with hypothyroidism. Here we document current practices of Polish physicians relating to the use of thyroid hormones in hypothyroid and euthyroid patients. Members of the Polish Society of Endocrinology were invited to participate in the web-based THESIS survey. In total 423 (54.6% of the 774 invited) physicians completed the survey. The majority of respondents (74.2%) would prescribe thyroid hormones foreuthyroid patients for certain indications, such as female infertility with elevated thyroid antibodies (63.4%), simple goitre (40.9%), unexplained fatigue (12.1%), obesity (9.7%), hypercholesterolaemia (9.0%), and depression (9.2%). Nearly all physicians (96.0%) declared that the treatment of choice for hypothyroidism is levothyroxine (LT4). However, around one-third (30.3%) were also using LT4 and liothyronine (LT3) combination treatment; LT3 alone was rarely prescribed (1.7%), and none prescribed desiccated thyroid extract. The majority of respondents preferred LT4 tablets. Among alternative formulations, liquid LT4 was most commonly recommended for patients unable to take LT4 in the fasting state (26.0%) and patients with malabsorption (19.9%). Respondents considered prescribing dietary supplements (such as selenium and iodine) in hypothyroid patients with coexisting autoimmune thyroiditis (29.6%) or at the patients' request (32.2%). LT4 + LT3 combination therapy was used by 32.2% when symptoms persisted notwithstanding normal serum TSH concentration. Psychosocial factors, comorbidities, and the burden of chronic disease were considered as the most likely causes of persistent symptoms. Apart from clinical practice recommendations, other factors influence the thyroid hormone therapy patterns. Moreover, certain areas of clinical practice were identified (the use of thyroid hormones in euthyroid subjects and the use of dietary supplements), which are not in accordance with the current evidence.

Analysis of metabolomics profile in hypothyroid patients before and after thyroid hormone replacement.

The serum metabolic changes occurring during the transition from hypothyroidism to euthyroidism are not known. This study aimed to determine the metabolomic profile in hypothyroid patients before (HypoT0) and after (HypoT1) euthyroidism achieved through levothyroxine (L-T4) treatment. Eighteen patients with overt primary hypothyroidism were recruited for the study. All patients were treated with L-T4 to achieve euthyroidism. Thyrotropin (TSH), free thyroxine (FT4), free triiodothyronine (FT3) and metabolomics profiles were measured before and after 3months of treatment. The euthyroid control group consisted of 28 healthy volunteers. Metabolomics analysis was performed using Nuclear Magnetic Resonance (NMR) spectroscopy. 1H NMR-based metabolomics profiling of patients with newly diagnosed hypothyroidism (HypoT0) showed significantly higher levels of citrate, creatinine, glycerol, myo-inositol and serine, and lower levels of proline and taurine compared to controls. Interestingly, some metabolic changes were persistent three months after pharmacological treatments, despite normal serum TSH and thyroid hormone concentrations (HypoT1). When an Orthogonal Partial Least Squares Discriminant Analysis (OPLS-DA) model was built to evaluate possible differences in the metabolic profile between HypoT0 and HypoT1, the data obtained were not significantly different. These results suggest that metabolic changes in the patients with hypothyroidism may persist after normalization of serum levels of FT3, FT4, and TSH, which currently represent the gold standard in laboratory testing for diagnosis and evaluation of thyroid pathology. So, the metabolomics approach may contribute to integrate classical hormone assays and to determine the euthyroid status achievement with greater efficacy.

The Normal TSH Reference Range: What Has Changed in the Last Decade?

Serum TSH assessment is the most sensitive screening test for the diagnosis of thyroid dysfunction in the absence of pituitary or hypothalamic disease. This test has been used increasingly in the last decade to detect subclinical thyroid dysfunction (STD). Recent data suggest that STD is a common disorder that may be associated with important adverse events (1–5). The American Association of Clinical Endocrinologists (AACE) and American Thyroid Association (ATA) 2012 guidelines recommend treatment of subjects with persistent increased serum TSH levels 10 mIU/L and undetectable serum TSH ( 0.1 mIU/L) (6, 7). The treatment of mild thyroid hormone excess (TSH 0.1–0.4 mIU/L) ordeficiency (serumTSH 10mIU/L) is controversial (1,2). However, what is the normal TSH reference range? Obviously, this issue is critical in deciding whether or not to treat patients with mild STD and in identifying individuals with high-normal or low-normal serum TSH. It is also important in defining the TSH target level in patients receiving thyroid hormone replacement therapy. In 2002, the National Health and Nutrition Examination Survey (NHANES) III, a US population-based study, evaluated the normal TSH range in the “thyroid disease-free adult population” (8).Theauthors excludedsubjectswith risk factorsandafamilyhistoryofthyroiddysfunction,self-reported thyroid disease or goiter, and thyroid autoimmunity. The study suggested that 95% of the US disease-free population had a serum TSH concentration between 0.45 and 4.12 mIU/L (8). However, TSH values did not have a Gaussian distribution because the curve was skewed by individuals with occult autoimmune thyroid dysfunction despite negative thyroid peroxidase antibodies (9). In 2005, the National Academy of Clinical Biochemistry (NACB) recommended that thyroidultrasonographybeperformedineuthyroidsubjects to exclude the presence of occult thyroid autoimmunity in order to define the serum TSH reference interval more accurately (10). They suggested that the upper limit of the TSH reference range be lowered to 2.5 mIU/L (10). The upper and lower limits of the normal serum TSH concentration continue to be debated by expert clinical thyroidologists. In 2005, two back-to-back articles appeared in the JCEM: one article, by Wartofsky and Dickey (11), favored a narrower TSH reference range, but according to the other, by Surks et al (12), the TSH range should remain unchanged. It should be mentioned that the sensitivity and specificity of TSH assays can affect the evaluation of serum TSH because some assays may detect biologically inactive circulating TSH isoforms (1). The upper TSH reference limit has progressively declined over the last decade thanks to more sensitive TSH assays, more accurate thyroid antibody tests, and a more accurate selection of the reference population. Different TSH cut-off limits have been reported in population-based studies conducted in various countries (1). Subsequent findings confirmed that ethnicity, iodine intake, gender, age, and body mass index can influence the reference range of serum TSH. In fact, the normal TSH upper limit was lower in African Americans (3.6 mIU/L) than in Mexican Americans or Caucasians (4.2 mIU/L) (8). Reanalysis of these data 5 years later showed that the upper limit of normal serum TSH at the 97.5th percentile was 3.5 mIU/L in individuals 20–29 years old, 4.5 mIU/L in those 50–59 years old, and 7.5 mIU/L in those older than 80 years (13). Variations in thyroid function within the reference range have been associated with body weight in several cross-sectional and longitudinal studies (14). Moreover, serum TSH levels at the upper limit of the normal range have been found in obese adults and have been positively correlated with body mass index (14).

Management of Differentiated Thyroid Cancer in the Presence of Resistance to Thyroid Hormone and TSH-Secreting Adenomas: A Report of Four Cases and Review of the Literature

An increased or normal serum TSH concentration, despite elevated thyroid hormone levels, is observed in resistance to thyroid hormone (RTH) and TSH-secreting adenomas (TSHomas). When coexistent with a differentiated thyroid cancer (DTC), maintenance of a suppression of TSH is challenging. The aim of the study was to discuss the pitfalls arising from the failure to suppress TSH secretion in DTC and the strategies for proper treatment of DTC in association with RTH and TSHoma. Four unusual cases of DTC associated with TSHoma (2 cases), RTH (1 case), and an elevated TSH of unknown etiology (1 case) are presented, and the literature is reviewed. Although a persistent mild TSH elevation may not be a risk factor for the development of DTC, it represents an important problem during the treatment of DTC. Aggressive treatment options should be applied in the proper order to prevent tumor recurrence and persistence in the absence of ideal TSH suppression. Although there is no agreed consensus regarding the management of DTC in the presence of persistent hyperthyrotropinemia, complete tumor removal followed by radioablation and attempts to reduce the serum TSH to the lowest tolerable level are recommended. The outcomes in the reported cases have not been unfavorable, despite the persistence of nonsuppressed TSH.

Subclinical Hypothyroidism in Pregnancy: Intellectual Development of Offspring

The effects of maternal subclinical hypothyroidism (M-SCH) on the neuropsychological development of the offspring are not clear. We evaluated the intellectual development of children of mothers who had M-SCH during the pregnancy for these children. Sixty-two children were recruited. After excluding those age < 4 or age > 15, 44 were enrolled. The mothers of these children were part of a sub-pool of 90, of 441 hypothyroid women of reproductive age seen in Tehran endocrine clinics between 1991 and 2003 and who were observed during gestation. Mothers were receiving levothyroxine (LT4) before gestation. Mothers of 19 children (control group) had normal serum thyrotropin (TSH) during the pregnancy that produced these children. Mothers of the other 25 children had increased TSH during the comparable pregnancy. Nineteen mothers had M-SCH (case group) and six had overt hypothyroidism. Serum TSH and free T4 (FT4) and urine iodine were measured, and seven cognitive performance and intelligence quotient (IQ) tests were performed. Case children were similar to control children with respect to gender, age, parental education, maternal age at time of pregnancy and at the time of their hypothyroidism, percent mothers having thyroid peroxidase antibodies, LT4 dose of mothers during pregnancy, gestational age at delivery, birth weight, and duration of breast feeding. Maternal TSH (mean ± standard deviation) in the case group during their mother's pregnancies was 11.3 ± 5.3 and 1.4 ± 1.0 mU/L in the controls (p < 0.001). Serum TSH, FT4 and urinary iodine concentrations were similar in the two groups. Total IQ, performance IQ, and verbal IQ were similar, being 120 ± 14, 117 ± 12, and 121 ± 16, respectively, in the case group and 121 ± 11, 120 ± 7, and 117 ± 15 in the control group. Cognitive performance tests were similar in both groups. No relationships were observed between variables and IQ except for education level of the mother and neonatal weight. IQ level and cognitive performance of children born to LT4-treated hypothyroid mothers is similar in those whose mothers have M-SCH during pregnancy compared with those whose mothers have normal serum TSH concentrations during pregnancy.

Endogenous Thyrotropin and Triiodothyronine Concentrations in Individuals with Thyroid Cancer

Thyroid hormone suppression therapy is associated with decreased recurrence rates and improved survival in patients with differentiated thyroid cancer. Recently higher baseline thyrotropin (TSH) levels have been found to be associated with a postoperative diagnosis of differentiated thyroid cancer. Our objective was to confirm whether preoperative TSH levels were higher in patients who were diagnosed with differentiated thyroid cancer after undergoing thyroidectomy, compared with patients who were found to have benign disease. We also sought to determine whether thyroid hormone levels were lower in the patients with malignancy. The study was a retrospective analysis of a prospective study. The study setting was the General Clinical Research Center of an Academic Medical Center. Participants were 50 euthyroid patients undergoing thyroidectomy. Thyroxine, triiodothyronine (T(3)), and TSH levels were documented in patients prior to their scheduled thyroidectomy. Following thyroidectomy, patients were divided into those with a histologic diagnosis of either differentiated thyroid cancer or benign disease. Preoperative thyroid profiles were correlated with patients' postoperative diagnoses. All patients had a normal serum TSH concentration preoperatively. One-third of the group was diagnosed with thyroid cancer as a result of their thyroidectomy. These patients had a higher serum TSH level (mean = 1.50 mIU/L, CI 1.22-1.78 mIU/L) than patients with benign disease (mean = 1.01 mIU/mL, CI 0.84-1.18 mIU/L). There was a greater risk of having thyroid cancer in patients with TSH levels in the upper three quartiles of TSH values, compared with patients with TSH concentrations in the lowest quartile of TSH values (odd ratio = 8.7, CI 2.2-33.7). Patients with a thyroid cancer diagnosis also had lower T(3) concentrations measured by liquid chromatography tandem mass spectrometry (mean = 112.6 ng/dL, CI 103.8-121.4 ng/dL) than did patients with a benign diagnosis (mean 129.9 ng/dL, CI 121.4-138.4 ng/dL). These data confirm that higher TSH concentrations, even within the normal range, are associated with a subsequent diagnosis of thyroid cancer in individuals with thyroid abnormalities. This further supports the hypothesis that TSH stimulates the growth or development of thyroid malignancy during its early or preclinical phase. We also show for the first time that patients with thyroid cancer also have lower T(3) levels than patients with benign disease.

L-Thyroxine Requirement in Patients with Autoimmune Hypothyroidism and Parietal Cell Antibodies

Hypothyroid patients on l-T(4) therapy may require replacement doses exceeding the theoretical needs to normalize serum TSH due to low patient compliance, drugs interference, and malabsorption. We examined whether autoimmune gastritis might cause increased l-T(4) requirement in patients with autoimmune thyroiditis receiving l-T(4) replacement. We studied 391 patients with clinical or subclinical hypothyroidism from autoimmune thyroiditis who had achieved normal serum TSH concentration (0.3-3.0 microU/ml) under l-T(4) for at least 6 months. Patients were screened for serum parietal cell antibodies (PCA) as a marker of autoimmune gastritis, and the PCA status was correlated with the l-T(4) dose. We also studied a group of 60 patients receiving l-T(4) replacement after total thyroidectomy. PCA-positive (155 of 391) and PCA-negative (236 of 391) patients did not differ for pretherapy serum TSH levels and thyroid volume. The l-T(4) requirement was significantly (P = 0.002) higher in PCA-positive (1.24 +/- 0.40 microg/kg x d) than in PCA-negative patients (1.06 +/- 0.36 microg/kg x d), and a significant positive correlation was found between l-T(4) requirement and serum PCA levels. Among PCA-positive patients, l-T(4) requirement was even higher in those with proven gastritis (1.52 +/- 0.40 microg/kg x d) compared with those without gastric damage (1.15 +/- 0.33 microg/kg x d) (P < 0.0001). The increased l-T(4) requirement was confirmed also in PCA-positive thyroidectomized patients (1.81 +/- 0.27 microg/kg x d) compared with PCA-negative thyroidectomized patients (1.52 +/- 0.24 microg/kg x d). Independent variables affecting l-T(4) requirement were PCA and serum TSH at diagnosis. Autoimmune gastritis is an additional factor affecting l-T(4) requirement in patients with autoimmune thyroiditis. Serum PCA measurement should be considered in patients with an unexplained high requirement of l-T(4).

Impact of continuing metformin treatment during pregnancy in polycystic ovary syndrome (PCOS) patients

Impact of continuing metformin treatment during pregnancy in polycystic ovary syndrome (PCOS) patients

Serum Thyrotropin In Primary Hypothyroidism: A Reliable And Accurate Predictor Of Optimal Daily Levothyroxine Dose

To assess the reliability and accuracy of the predicted optimal daily levothyroxine (LT4) dose based on pretreatment serum thyrotropin (thyroid-stimulating hormone or TSH) level in primary hypothyroidism. We examined the relationships between the actual daily LT4 dose required to attain and maintain normal serum TSH concentration and the calculated daily LT4 dose, based on previously established correlations with pretreatment serum TSH concentrations, in 108 consecutive patients with primary hypothyroidism treated in an endocrinology clinic during an 18-month period. Highly significant correlations were noted between the optimal daily LT4 dose and the calculated dose based on either logarithmic regression (r = 0.86; P<0.00001) or linear regression (r = 0.83; P<0.00001). Moreover, the actual mean daily LT4 dose (133 +/- 4 mg) approximated the mean doses predicted by both regression analyses (129 +/- 5 mg and 126 +/- 5 mg, respectively) and was identical in many of the study subjects. The predicted optimal daily LT4 dose based on pretreatment serum TSH level provides a reliable and accurate approximation of the final optimal LT4 dose in patients with primary hypothyroidism and therefore may be a more convenient and cost-effective therapeutic approach than the current traditional clinical practice.

Is excessive weight gain after ablative treatment of hyperthyroidism due to inadequate thyroid hormone therapy?

There is controversy about the correct dose and form of thyroid hormone therapy for patients with hypothyroidism. Despite restoration of serum thyrotropin (TSH) concentrations to normal, many patients complain of excessive weight gain. We have compared weight at diagnosis of hyperthyroidism with that when euthyroid, evidenced by a stable, normal serum TSH concentration, with or without thyroxine (T4) replacement therapy, in patients treated with an 18-month course of antithyroid drugs (43 patients), surgery (56 patients), or 13I (34 patients) for Graves' disease. In addition, weights were recorded before and after treatment of 25 patients with differentiated thyroid carcinoma by total thyroidectomy, 131I, and long-term T4 suppressive therapy, resulting in undetectable serum TSH concentrations. Mean weight gain in patients with Graves' disease who required T4 replacement therapy following surgery was significantly greater than in those of the same age, sex, and severity of hyperthyroidism rendered euthyroid by surgery (3.9 kg) (p < 0.001) or at the end of a course of antithyroid drugs (4.1 kg) (p < 0.001). Weight gain was similar in those requiring T4 replacement following surgery or 131T therapy (10.4 versus 10.1 kg). In contrast, ablative therapy combined with suppression of TSH secretion by T4 in patients with differentiated thyroid carcinoma did not result in weight gain. The excessive weight gain in patients becoming hypothyroid after destructive therapy for Graves' disease suggests that restoration of serum TSH to the reference range by T4 alone may constitute inadequate hormone replacement.

SUBCLINICAL THYROTOXICOSIS

Subclinical thyrotoxicosis is defined as low serum thyrotropin (TSH) and normal serum thyroid hormone concentrations. It must be distinguished from nonthyroidal illness and secondary hypothyroidism. The most common causes are excessive thyroid hormone therapy, autonomously functioning thyroid adenoma, multinodular goiter, and Graves' disease, but many patients have no evident thyroid disease. A few patients have minor symptoms and signs of hyperthyroidism. The likelihood of progression to overt thyrotoxicosis is low, and many patients have normal serum TSH concentrations weeks or months later. Treatment should be based on consideration of the cause of the subclinical thyrotoxicosis, and whether the patient has any clinical manifestations of thyroid hormone excess or underlying problems likely to be aggravated by small increases in thyroid secretion.

Recombinant human thyrotropin is a potent stimulator of thyroid function in normal subjects.

Recombinant human TSH (rhTSH) is known to stimulate 131I uptake and thyroglobulin (Tg) release from the postoperative remnant and metastases in thyroid cancer patients, but its effects on serum thyroid hormone and Tg concentrations in normal subjects have not been reported. Before using rhTSH in the management of thyroid disorders other than cancer, the thyroid response to rhTSH in normal subjects must be assessed. Six subjects, two men and four women, without evidence of thyroid disease, including normal serum free T4 index and TSH concentrations and negative tests for antithyroid peroxidase and Tg, were studied. Each received 0.1 mg rhTSH, im, 11% of the lowest dose that has been administered to thyroid cancer patients. Blood was obtained before; 2, 4, and 8 h after; and 1, 2, 3, 4, 7, and about 3 weeks after rhTSH administration. Serum TSH significantly increased at 2 h (mean +/- SE, 2.4 +/- 0.9 to 40.7 +/- 7.4 mU/mL), peaked at 4 h (50.9 +/- 9.3), remained significantly elevated for 1 day, and was significantly below baseline (0.8 +/- 0.5) 7 days after rhTSH administration. Serum T3 increased significantly at 4 h (115 +/- 4 to 190 +/- 14 ng/dL), peaked at 24 h (217 +/- 23 ng/dL), and remained significantly elevated for 3 days (151 +/- 12 ng/dL). Serum T4 increased significantly at 8 h (7.3 +/- 0.2 to 9.8 +/- 0.4 micrograms/dL), peaked at 24 h (11.2 +/- 0.5 micrograms/dL), and remained significantly elevated for 4 days (9.4 +/- 0.5 micrograms/dL). Serum Tg did not change for the first 8 h, increased significantly at 1 day (15.9 +/- 3.9 to 34.7 +/- 6.0 ng/mL), peaked at 2 days (44.2 +/- 7.0 ng/mL), and remained significantly elevated for 4 days (37.7 +/- 13.7 ng/mL). All values returned to baseline at 3 weeks. TSH antibodies were not detected at 3 weeks. A single dose of 0.1 mg rhTSH is a potent stimulator of thyroid function in normal subjects. rhTSH may be a useful agent to test thyroid reserve and for use in clinical settings that require direct thyroid stimulation.

Thyroiditis after pregnancy loss.

We present a case series evaluating the development and characteristics of thyroiditis following pregnancy loss. Five women were followed prospectively with measurement of thyroid function and antithyroid antibodies after pregnancy loss. Serum TSH concentrations were measured by immunoradiometric assay and antithyroid antibodies by RIA and hemagglutination techniques. All women had normal serum TSH concentrations before conception or at the time of pregnancy loss, and all but one had positive antithyroid antibodies. Pregnancy loss occurred between 5-20 weeks gestation because of ectopic pregnancy or either spontaneous or elective abortion. Two women had subclinical hypothyroidism with peak serum TSH values of 8.7 mU/L and 5.4 mU/L at 2 and 7 months after pregnancy loss, respectively. Three women had clinical hyperthyroidism with serum TSH values < or = 0.2 mU/L diagnosed between 3-11 months after pregnancy loss followed subsequently by a hypothyroid phase. Painless thyroiditis within 1 yr of pregnancy loss in these women suggests that the immunological changes of a short-term gestation may be sufficient to lead to thyroiditis.

Evidence for the secretion of thyrotropin with enhanced bioactivity in syndromes of thyroid hormone resistance.

Resistance to thyroid hormone (RTH) is a rare genetic disorder associated with diverse mutations in the thyroid hormone receptor beta-gene. TSH-dependent thyroid hyperstimulation, leading to goiter and elevated thyroid hormone levels, is a characteristic feature of RTH. However, about 60% of untreated resistance patients have circulating TSH levels within the normal range, raising the possibility that the biological activity of TSH is altered. We, therefore, assayed the bioactivity of circulating TSH in 11 patients from 8 different kindreds with RTH, measuring cAMP production in Chinese hamster ovary cells transfected with the recombinant human TSH receptor as well as in FRTL-5 cells. The ratio of biologically active vs. immunoreactive TSH (B/I) was significantly higher in RTH patients than in 8 normal controls [TSH B/I, 4.2 +/- 0.9 (range, 2.2-11.9) vs. 1.3 +/- 0.2 (range, 0.6-2.1)]. TSH released in response to TRH had a bioactivity similar to that of circulating TSH under basal conditions. On the contrary, supraphysiological doses of T3 normalized the B/I ratio of circulating TSH. Concanavalin-A chromatography of TSH from RTH patients showed the presence of circulating forms with altered carbohydrate branching. Our data indicate that the bioactivity of circulating TSH in thyroid hormone resistance syndromes is enhanced and can be normalized after T3 administration. These findings may account for the occurrence of goiter and elevated thyroid hormone levels in RTH patients despite normal serum TSH concentrations.

Thyroid ultrasonography in patients with a previous episode of amiodarone induced thyrotoxicosis.

Amiodarone induced thyrotoxicosis (AIT) occurs most frequently in euthyroid patients with nodular goiter or Graves' disease due to release of iodine from this iodine rich drug. However, some cases of AIT have been attributed to an inflammatory process of the thyroid gland due to amiodarone itself. We have studied the echographic pattern of the thyroid in 11 euthyroid patients who had an episode of AIT 32.4 +/- 3.6 months earlier due to amiodarone induced thyroiditis. There was a significant increase in dyshomogeneous echo patterns and hyperechogenecity which suggests fibrotic lesions. These findings were similar to those observed in 10 euthyroid patients who 77 +/- 12 months earlier had an episode of subacute thyroiditis (SAT). Thyroid volumes of control subjects and patients with a history of AIT and SAT were 10.9 +/- 1.4, 8.7 +/- 1.4 and 9.8 +/- 1.7, in the order. These values were not significantly different. These echographic findings, normal serum thyroid hormone and TSH concentrations and the absence of circulating antithyroid peroxidase antibodies suggest that underlying thyroid autonomy and Graves' disease were not the cause of the previous episode of AIT. The presence of hyperechogenic and dyshomogeneous patterns appears the result of the healing of the inflammatory AIT process.

A long-term follow-up study of patients with non-toxic diffuse goitre in Japan.

Although non-toxic diffuse goitre is a common disorder, little is known of the clinical course of patients. We therefore decided to investigate the long-term clinical outcome of patients with non-toxic diffuse goitre. A retrospective study. Of 850 patients with non-toxic diffuse goitre who met our criteria and were seen in our thyroid clinic between 1977 and 1985, 108 who had been followed for from 5 to 14 years (mean 8 years) were entered in this study. All patients fulfilled our criteria having soft diffuse goitres, normal serum TSH and T4 concentrations, and undetectable antithyroglobulin and antithyroid microsomal antibodies. A family history of thyroid disease was obtained and the occurrence of Graves' ophthalmopathy was noted. Serum TSH and T4 concentrations, and antithyroglobulin and antithyroid microsomal antibodies were measured during the follow-up period. Thyroidal radioactive iodine uptake (RAIU), serum free T4 and free T3 concentrations, and TSH binding inhibitory immunoglobulin (TBII) activities were determined in all patients who were subsequently found to have abnormal serum TSH or T4 concentrations or signs of Graves' ophthalmopathy. Thirty-six of the 108 patients (33%) had a family history of autoimmune thyroid disease. Elevated serum T4 or free T4 concentrations and depressed serum TSH concentrations were found in six patients during the follow-up period. Hyperthyroid Graves' disease was diagnosed in four of the six patients, subacute thyroiditis in one, and transient post-partum thyrotoxicosis in one. Hypothyroidism was found in one patient who was diagnosed as having transient post-partum hypothyroidism. Euthyroid Graves' disease was diagnosed in one patient. Furthermore, six of these eight patients had a family history of autoimmune thyroid disease in first-degree relatives. During a prolonged follow-up period of patients with non-toxic diffuse goitre, Graves' disease was found in five of 108 patients (four hyperthyroid Graves' and one euthyroid Graves'), post-partum thyroid dysfunction in two, and subacute thyroiditis in one. Six of these eight patients had a family history of autoimmune thyroid disease in first-degree relatives. Long-term follow-up is necessary for patients with non-toxic diffuse goitre, especially those who have a family history of autoimmune thyroid disease.

Low serum free thyroxine index in ambulating elderly is due to a resetting of the threshold of thyrotropin feedback suppression.

Subnormal free T4 index (FT4I) values (less than 80) with inappropriately normal serum TSH concentrations that could not be attributed to illness or drugs were found in 2.5% of ambulating elderly clinic patients. Six such individuals (three men and three women, aged 68.8 +/- 4.8 yr) were selected for their persistent thyroid test abnormalities and were sex and age matched to six subjects (67.7 +/- 4.9 yr) with normal FT4I (greater than 90) and TSH levels. The former also had low serum total T4 (TT4) and rT3 (TrT3) concentrations, but total T3 (TT3) and basal TSH values were normal and did not differ between the groups. Responses of ACTH, LH, FSH, TSH, and PRL to stimulation with CRH, GnRH, and TRH showed no differences between the two groups, indicating that the normal TSH concentration, inappropriate for the low FT4I level, is not due to generalized hypothalamic or pituitary dysfunction. Administration of 3 g iopanoic acid (IOP) daily for 3 days produced significant increases in the TT4 and TrT3 concentrations to the same degree in both groups. Also, in both groups the IOP-induced suppression of T4 to T3 conversion in the pituitary gland provoked similar increases in basal TSH (280 +/- 47% and 288 +/- 33%) and TSH secretion in response to TRH (173 +/- 7% and 156 +/- 13%). These results indicate that the low FT4I is not the consequence of reduced pituitary TSH reserve. In addition, evidence for normal thyroid gland reserve and the secretion of TSH of normal biological activity was obtained by comparing the acute iodothyronine responses to TRH-induced TSH release in both groups. It is concluded that the normal serum TSH concentration, inappropriate for the low FT4I value in some elderly subjects, is due to an apparent resetting of the thyroid hormone feedback regulation threshold of TSH secretion. It may, in turn, be the result of enhanced pituitary conversion of T4 to T3 or increased T4 uptake by the thyrotrophs.

Decreased mononuclear leukocyte TSH responsiveness in patients with major depression

A subgroup of individuals with major depressive disorder have an impaired thyrotropin (TSH) response to thyrotropin-releasing hormone (TRH). The molecular relationship between the mechanism of this “blunted” TSH response and depression is unknown. Numerous recent studies have characterized similarities and interactions between the immune and neuroendocrine systems. As the immune system both produces and responds to TSH, we utilized a peripheral blood leukocyte system to compare immunoreactive (ir)-TSH responsiveness in 10 adult patients (1 man, 9 women) with Research Diagnostic Criteria for major depressive disorder to that of 9 control subjects. All subjects had normal baseline serum TSH and T4 concentrations. Isolated mononuclear leukocytes were treated in vitro with either 0.5 μg/ml staphylococcal enterotoxin A (SEA), 50 μg/ ml TRH, or no stimulant. After incubation, the cells were monitored for ir-TSH production by indirect immunofluorescence and reverse hemolytic plaque assay using antisera to TSH-β. The culture supernates were analyzed by TSH radioimmunoassay. SEA- and TRH-treated cell cultures from depressed individuals had significantly fewer immunofluorescent positive cells, as well as significantly fewer and smaller plaques, than did similarly treated leukocytes from control subjects. The increase in supernatant ir-TSH was significantly less in TRH-treated cultures from depressed patients as compared to normals ( p < 0.05). These results suggest that examination of mononuciear leukocyte TSH production may reflect an altered state of neuroendocrine function and may thus be a useful marker for major depressive disorder.

Phenytoin and thyroid hormone action.

Circulating free thyroid hormone concentrations are reduced in subjects taking long-term phenytoin, a finding at variance with their euthyroid clinical state and normal serum TSH concentration. It is suggested, therefore, that phenytoin may modify the cellular effects of thyroid hormones. In order to examine the influence of phenytoin on thyroid hormone action in the pituitary gland we studied its effect on the binding of tri-iodothyronine (T3) to isolated nuclei prepared from rat anterior pituitary tissue. Phenytoin inhibited the nuclear binding of T3 in a dose-dependent fashion. Phenytoin also partially inhibited thyrotrophin-releasing hormone-stimulated TSH release from cultured rat anterior pituitary cells. These studies provide evidence for a direct effect of phenytoin on the thyrotroph mediated via nuclear T3 receptor binding.

Natural history of thyroid function in diabetics with impaired thyroid reserve: a four year controlled study.

An attempt was made to compare the natural history of thyroid function in 80 diabetics having raised serum TSH concentrations (median 8.9 mU/l, range 5.8-46.3 mU/l) but serum T4 concentrations within the normal range (Group 1), and in 59 diabetics having normal serum TSH (median 1.9 mU/l, range 0.8-4.7 mU/l) and T4 concentrations (Group 2). Thyroid microsomal antibodies were present initially in 65% of patients in Group 1 and 15% of patients in Group 2. By 1981, 59 patients (74%) in Group 1 and 47 patients (80%) in Group 2 had been followed for a mean +/- SD duration of 4.2 +/- 1.8 and 4.2 +/- 1.5 years, respectively. Hypothyroidism developed in 9 patients in Group 1, but none from Group 2. Of patients in Group 1, hypothyroidism developed at a rate of 5% per annum in those with thyroid microsomal antibodies, but only 1% per annum in those without antibodies. Therefore, the risk of development of hypothyroidism is greatest in diabetics having both elevated serum TSH concentrations and thyroid microsomal antibodies and such patients should have regular review of thyroid function. Either risk factor alone appears to be a poor predictor of development of hypothyroidism.