Normal Serum Thyroid Hormone Levels Research Articles

A Review on Hashimoto’s Thyroiditis

Hashimoto's thyroiditis (HT) is an autoimmune thyroid disorder first described by Japanese physician Haraku Hashimoto in 1912 characterized by lymphocytic infiltration of the thyroid parenchyma and is influenced by immune system instability. The onset of autoimmunity may be influenced by innate and acquired immune responses. Thyroid autoantibodies (TAbs) are the primary biochemical feature. Epidemiological studies show AITD (autoimmune thyroid disease) risk is higher in women and is age-related. Risk factors include high iodine consumption, selenium insufficiency, infectious disorders, and specific medications. Genetic predisposition and environmental factors also contribute to HT. Pregnancy and sex steroids play a role in the development of autoimmune thyroiditis, with older women being more susceptible. The immune system is modified during pregnancy, with progesterone playing a significant role. About 20% of postpartum thyroiditis patients eventually develop HT. The symptoms include dysphonia, dyspnea, and dysphagia, with primary hypothyroidism causing greater systemic symptoms. Diagnosis involves circulating thyroid-specific antibodies, ultrasound examination, increased thyroid stimulating hormone, and normal serum thyroid hormone levels. Ultrasonography is crucial for diagnosing Hashimoto's thyroiditis, distinguishing it from other thyroid disorders like Graves' disease (GD). The treatment comprises levothyroxine, which effectively lowers thyroid volume, as well as vitamin D deficiency and replacement. Autoimmune thyroiditis (AIT) surgery has traditionally been reserved for people who have discomfort or compressive symptoms from goitre or co-existing malignant thyroid nodules. Thyroidectomy has lately been advocated as a treatment option for decreasing TPOAbs, as the presence of such antibodies is linked to a worse quality of life even in euthyroid patients.
 Keywords: Hashimoto’s thyroiditis (HT), Autoimmune thyroid disease (AITD), Autoimmune thyroiditis (AIT) Vitamin D , Levothyroxine

Real-time oxidative stress biomarkers measured in patients with Hashimoto’s thyroiditis—an electron paramagnetic resonance study

Although the role of presence of thyroid dysfunction for overproduction of free radicals has been elucidated, the data about the role of autoimmunity in Hashimoto’s thyroiditis (HT) to sustain the presence of oxidative stress despite the normal serum thyroid hormone levels are scarce. The present study aimed by using electron paramagnetic resonance spectroscopy (EPR) methods to elucidate the radical mechanisms included in the pathogenesis of HT by following out the sera levels of some “real-time” oxidative stress biomarkers. We investigated 14 newly diagnosed patients with euthyroid HT and 35 subjects with HT treated with levothyroxine. Twenty-three healthy subjects were included as controls. All samples were measured in triplicate and presented as arbitrary units. We found statistically significant elevated levels of ascorbate radical (Asc•) in euthyroid HT patients and in HT patients treated with levothyroxine compared to controls. Reactive oxygen species (ROS) products were statistically higher in both studied patient groups compared to controls. Our study showed also statistically significant increases in the levels of registered nitric oxide radical (NO•) in both groups of HT patients compared to controls. Oxidative stress is increased similarly in both euthyroid HT and HT patients under treatment with LT4 and these data reinforce the idea that this is consequence of autoimmunity per se. Our results determine that the addition of antioxidants that includes vitamin C and vitamin E in the treatment plan of HT patients in all stages of disease will normalize the disbalance in oxidative stress biomarkers.

Euthyroid Sick Syndrome.

In this review, we discuss the characteristics, pathophysiology, and therapeutic implications of the euthyroid sick syndrome. Multiple mechanisms have been identified to contribute to the development of euthyroid sick syndrome, including alterations in the iodothyronine deiodinases, thyroid-stimulating hormone secretion, thyroid hormone binding to plasma protein, transport of thyroid hormone in peripheral tissues, and thyroid hormone receptor activity. The euthyroid sick syndrome appears to be a complex mix of physiologic adaptation and pathologic response to acute illness. The underlying cause for these alterations has not yet been elucidated. Treatment of the euthyroid sick syndrome with thyroid hormone to restore normal serum thyroid hormone levels in an effort to improve disease prognosis and outcomes continues to be a focus of many clinical studies, although currently available data do not provide evidence of a clear benefit of treatment.

Low-dose T₃ replacement restores depressed cardiac T₃ levels, preserves coronary microvasculature and attenuates cardiac dysfunction in experimental diabetes mellitus.

Thyroid dysfunction is common in individuals with diabetes mellitus (DM) and may contribute to the associated cardiac dysfunction. However, little is known about the extent and pathophysiological consequences of low thyroid conditions on the heart in DM. DM was induced in adult female Sprague Dawley (SD) rats by injection of nicotinamide (N; 200 mg/kg) followed by streptozotocin (STZ; 65 mg/kg). One month after STZ/N, rats were randomized to the following groups (N = 10/group): STZ/N or STZ/N + 0.03 μg/mL T3; age-matched vehicle-treated rats served as nondiabetic controls (C). After 2 months of T3 treatment (3 months post-DM induction), left ventricular (LV) function was assessed by echocardiography and LV pressure measurements. Despite normal serum thyroid hormone (TH) levels, STZ/N treatment resulted in reductions in myocardial tissue content of THs (T3 and T4: 39% and 17% reduction versus C, respectively). Tissue hypothyroidism in the DM hearts was associated with increased DIO3 deiodinase (which converts THs to inactive metabolites) altered TH transporter expression, reexpression of the fetal gene phenotype, reduced arteriolar resistance vessel density, and diminished cardiac function. Low-dose T3 replacement largely restored cardiac tissue TH levels (T3 and T4: 43% and 10% increase versus STZ/N, respectively), improved cardiac function, reversed fetal gene expression and preserved the arteriolar resistance vessel network without causing overt symptoms of hyperthyroidism. We conclude that cardiac dysfunction in chronic DM may be associated with tissue hypothyroidism despite normal serum TH levels. Low-dose T3 replacement appears to be a safe and effective adjunct therapy to attenuate and/or reverse cardiac remodeling and dysfunction induced by experimental DM.

Tissue-Specific Alterations in Thyroid Hormone Homeostasis in Combined Mct10 and Mct8 Deficiency

The monocarboxylate transporter Mct10 (Slc16a10; T-type amino acid transporter) facilitates the cellular transport of thyroid hormone (TH) and shows an overlapping expression with the well-established TH transporter Mct8. Because Mct8 deficiency is associated with distinct tissue-specific alterations in TH transport and metabolism, we speculated that Mct10 inactivation may compromise the tissue-specific TH homeostasis as well. However, analysis of Mct10 knockout (ko) mice revealed normal serum TH levels and tissue TH content in contrast to Mct8 ko mice that are characterized by high serum T3, low serum T4, decreased brain TH content, and increased tissue TH concentrations in the liver, kidneys, and thyroid gland. Surprisingly, mice deficient in both TH transporters (Mct10/Mct8 double knockout [dko] mice) showed normal serum T4 levels in the presence of elevated serum T3, indicating that the additional inactivation of Mct10 partially rescues the phenotype of Mct8 ko mice. As a consequence of the normal serum T4, brain T4 content and hypothalamic TRH expression were found to be normalized in the Mct10/Mct8 dko mice. In contrast, the hyperthyroid situation in liver, kidneys, and thyroid gland of Mct8 ko mice was even more severe in Mct10/Mct8 dko animals, suggesting that in these organs, both transporters contribute to the TH efflux. In summary, our data indicate that Mct10 indeed participates in tissue-specific TH transport and also contributes to the generation of the unusual serum TH profile characteristic for Mct8 deficiency.

Thyroid autoantibodies are rare in nonhuman great apes and hypothyroidism cannot be attributed to thyroid autoimmunity.

The great apes include, in addition to Homo, the genera Pongo (orangutans), Gorilla (gorillas), and Pan, the latter comprising two species, P. troglodytes (chimpanzees) and P. paniscus (bonobos). Adult-onset hypothyroidism was previously reported in 4 individual nonhuman great apes. However, there is scarce information on normal serum thyroid hormone levels and virtually no data for thyroid autoantibodies in these animals. Therefore, we examined thyroid hormone levels and TSH in all nonhuman great ape genera including adults, adolescents, and infants. Because hypothyroidism in humans is commonly the end result of thyroid autoimmunity, we also tested healthy and hypothyroid nonhuman great apes for antibodies to thyroglobulin (Tg), thyroid peroxidase (TPO), and the TSH receptor (TSHR). We established a thyroid hormone and TSH database in orangutans, gorillas, chimpanzees, and bonobos (447 individuals). The most striking differences are the greatly reduced free-T4 and free-T3 levels in orangutans and gorillas vs chimpanzees and bonobos, and conversely, elevated TSH levels in gorillas vs Pan species. Antibodies to Tg and TPO were detected in only 2.6% of adult animals vs approximately 10% in humans. No animals with Tg, TPO, or TSHR antibodies exhibited thyroid dysfunction. Conversely, hypothyroid nonhuman great apes lacked thyroid autoantibodies. Moreover, thyroid histology in necropsy tissues was similar in euthyroid and hypothyroid individuals, and lymphocytic infiltration was absent in 2 hypothyroid animals. In conclusion, free T4 and free T3 are lower in orangutans and gorillas vs chimpanzees and bonobos, the closest living human relatives. Moreover, thyroid autoantibodies are rare and hypothyroidism is unrelated to thyroid autoimmunity in nonhuman great apes.

Subclinical Thyroid Disease

Subclinical Thyroid Disease

Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal replacement, in the rat.

L-triiodothyronine (L-T3) is taken up and accumulated into red blood cells (RBC) by means of a specific carrier-mediated system. The aim of this study was to evaluate the reactivity of this system in relation to induced alterations in thyroid hormone (TH) supply. We investigated the kinetic parameters (Vmax, maximal velocity and Km, Michaelis constant) of washed-RBC L-T3 uptake 1) in thyroidectomized (TXT) rats, 2) in TXT rats administered with low doses of L-T4 (15 microg/kg/day x 14) to restore normal serum TH levels (REPL), 3) in TXT rats administered with high doses of L-T4 (200 microg/kg/day x 14) to achieve a large increase in serum TH levels (HIGH). Serum free T3 and T4 levels were significantly decreased in TXT rats (2.4 and 8.8 fold, respectively), not different in REPL rats and significantly increased in HIGH rats (2.4 and 3 fold, respectively) compared to sham-operated rats (SHAM). Both kinetics of RBC L-T3 uptake were significantly increased in TXT rats (Vmax+/-SE in pmol/min/10(8) cells=235.1+/-11.1, p<0.05 and Km+/-SE in nM=190.1+/-9.0, p<0.05), not different in REPL rats (Vmax=1 84.8+/-7.6 and Km=151.9+/-7.1) and significantly decreased in HIGH rats (Vmax=168.0+/-4.1, p<0.01 and Km=131.9+/-4.6, p<0.01) compared to SHAM rats (Vmax=197.7+/-5.8 and Km=160.9+/-6.1). These results show that kinetics of RBC L-T3 uptake are modified in response to defect or excess in circulating TH levels. Since RBC play likely a role of a buffer system, the changes in carrier-mediated influx of L-T3 could be seen as a compensatory mechanism that counteract the disturbances in the TH availability for the target tissues.

Catatony in Graves' disease

We report a 27-year-old female patient with prior history of Graves' disease and relapsing episodes of tachycardia, hyperpyrexia, muscular rigidity and coma. With the subsequent manifestation of an acute schizophreniform psychotic disorder unresponsive to neuroleptics, the primary syndrome was re-classified as febrile catatony. Hyperthyroidism was ruled out with normal serum thyroid hormone levels, as were toxic effects of thyrostatic treatment, drug-induced hypothyroidism and a malignant neuroleptic syndrome. All psychiatric symptoms subsided completely following subtotal thyroidectomy. Febrile catatatony has to be added to the spectrum of psychotic phenomena that may be caused by Graves' disease, irrespective of serum thyroid hormone levels.

Unexplained Disturbance in Body Weight Regulation: Diagnostic Outcome Assessed by Doubly Labeled Water and Body Composition Analyses in Obese Patients Reporting Low Energy Intakes

Subjects Ten patients who had long-term disturbances in body weight regulation, were referred over a 3-year period for obesity evaluation, and reported low energy intakes (<l,200kcal/day) Objective To ascertain whether these patients had a low energy expenditure and thus reduced energy requirement, and/or whether they were misreporting their energy intake. Design Comparison of outcome measures in referred patients and in obese control patients who did not report low energy intakes and disturbances in body weight regulation. Main outcome measures Low energy expenditure was evaluated with serum thyroid hormone levels, resting metabolic rate (RMR), thermic effect of food (TEF), and total energy expenditure (TEE) by doubly labeled water technique. Misreporting of energy intake was evaluated by comparing patients' self-reported energy intake with energy intake estimated by doubly labeled water and body composition analyses over a 14-day period. Statistical analyses performed Low energy expenditure was considered present in a patient if RMR or TEE was more than 15% below predicted values according to results from the control group. Patient group TEF was compared with TEF results observed in the control group. Results All patients had normal serum thyroid hormone levels. Eight patients had RMR and TEE values within 15% of predicted values and were substantially underreporting their energy intake. One patient had low TEE (−19%) and a normal RMR, a finding that implies a low level of physical activity. This patient also underreported energy intake as estimated by the doubly labeled water technique during the study (−38%). The 10th patient had a low RMR (−23.2%) and TEE (−25.0%), the mechanism of which was uncertain. This patient's reported food intake over the 14-day period was accurate but was less than her long-term intake over months or years as suggested by doubly labeled water TEE estimates. The TEF response in patients was not significantly different from that observed in the control group. Conclusions Underreporting of energy intake from foods is a frequent finding in patients with disturbances in body weight regulation who are referred for obesity evaluation. Severe underreporting may be detectable by means' of screening measures available to most dietitians. Low energy expenditure, due either to physical inactivity or to metabolic factors, is also observed. Modern evaluation methods provide new insights into patients with weight regulatory disturbances and at the same time stimulate important new research questions. J Am Diet Assoc. 1995; 95:1393-1400.

Lack of seasonal variation in abnormal TSH secretion in patients with seasonal affective disorder

The circadian variations in thyroid-stimulating hormone (TSH) secretion, with particular attention to the nocturnal serum TSH surge and the TSH response to thyrotropin releasing hormone (TRH), were measured in seven patients with seasonal affective disorder (SAD) and in eight normal controls. Both patients with SAD and normal controls were tested in fall/winter, when patients were suffering depressive symptoms, and in spring/summer, when patients were euthymic. The TRH tests were performed in the morning. In all tests, the mean peak TSH response to TRH was significantly lower in the patients with SAD than in the normal controls. No significant differences were observed in either group between spring/summer and fall/winter tests. At both periods, patients with SAD showed normal TSH levels in the morning, but did not experience a nocturnal TSH surge. In this group, morning and night TSH levels were similar. In contrast, normal controls showed significantly higher TSH levels at night than in the morning. Serum-free thyroid hormone levels were in the normal range in all subjects. Morning and night serum cortisol levels and 24-hour urinary cortisol concentrations were similar in all subjects. These data show that the secretion of TSH is impaired in SAD, regardless of the phase of the psychiatric disease. The low TSH response to TRH in the presence of normal serum thyroid hormone levels and the lack of the TSH nocturnal surge suggest that patients with SAD might be affected by mild central hypothyroidism.

Reduction in size of a thyrotropin- and gonadotropin-secreting pituitary adenoma treated with octreotide acetate (somatostatin analog).

TSH as well as alpha-subunit, secretion has been shown to decrease after the administration of the somatostatin analog octreotide acetate (SMS 201-995). We have studied a 59-yr-old, male patient with a TSH- and gonadotropin-secreting tumor who, because of severe cardiomyopathy, was treated with long-term somatostatin analog rather than surgical resection of the pituitary tumor. Thirteen weeks of treatment with thrice daily sc injection of 100 micrograms octreotide acetate resulted in decreased TSH and alpha-subunit secretion, normal serum thyroid hormone levels, reduction in LH and testosterone level, and significant tumor size reduction. Long-term treatment for 51 weeks has not been associated with any significant side effects. We have shown that octreotide acetate may be a therapeutically valuable modality for certain patients with neoplastic inappropriate secretion of TSH (NIST). A probable effect of octreotide acetate on neoplastic gonadotropes, as evidenced by the reduction of the LH level with a concomitant decrease in testosterone level, is, likewise, suggested.

Tsh Secretion In Cushing's Syndrome: Relation To Glucocorticoid Excess, Diabetes, Goitre, And The ‘Sick Euthyroid Syndrome’

Thyrotrophin (TSH) secretion was studied in 63 patients with Cushing's syndrome (53 patients with pituitary dependent Cushing's disease, eight with adrenocortical tumours, and two with the ectopic ACTH syndrome). Prior to treatment, TSH response to 200 micrograms of TRH intravenously was significantly decreased compared to controls; TSH response was 'flat' (increment less than 2 mU/l) in 34 patients (54%). Patients with a flat response to TRH had significantly higher morning and midnight cortisol levels than patients with a TSH response of 2 mU/l and more; this was not due to differences in serum thyroid hormone levels. Basal TSH, TSH increment after TRH, and stimulated TSH value, but not serum triiodothyronine, were correlated with cortisol measurements (0800 h serum cortisol, midnight cortisol, and urinary free corticoid excretion). After exclusion of 40 patients with additional disease (severe systemic disease, diabetes mellitus, or goitre), cortisol-TSH correlations were even more pronounced (r = -0.73 for midnight cortisol and stimulated TSH levels), while in the patients with additional complications, these correlations were slight or absent. Successful treatment in 20 patients was associated with a rise in thyroid hormone levels and the TSH response to TRH. These results indicate that (1) the corticoid excess but not serum T3 is the principal factor regulating TSH secretion in Cushing's syndrome, (2) a totally flat response to TRH is rare, and (3) TSH suppression and lower than normal serum thyroid hormone levels are reversible after treatment. Since factors like severe systemic disease, diabetes mellitus and goitre also affect TSH secretion, they tend to obscure the statistically significant correlations between cortisol excess and TSH secretion.

Thyroid dysfunction in a prospectively followed series of patients with progressive systemic sclerosis

Thirty-nine patients with progressive systemic sclerosis (PSS) in stable clinical conditions were extensively evaluated for the presence of thyroid disease. Two patients had previously undetected hypothyroidism while 7 additional patients had normal serum thyroid hormone levels but an exaggerated TSH response to thyrotropin-releasing hormone (TRH) administration, consistent with subclinical hypothyroidism. Four of the 9 subjects with abnormal TRH responses had positive antithyroid antibodies and of the remaining 5, 4 had been on chlorambucil or prednisone. Basal TSH and TSH response to TRH were significantly higher in PSS patients as a group when compared to a control group and increased with increasing duration of PSS. Serum antithyroid antibodies (antithyroglobulin and/or antimicrosomal antibodies) were positive in 18% and thyroid scans were abnormal in 18% of the patients. The euthyroid sick syndrome was not seen. Our findings indicate an increased frequency of, sometimes previously unsuspected, clinical and subclinical hypothyroidism in stable PSS patients which appears to be autoimmune in nature and becomes more prevalent with increased PSS duration. Careful and regular monitoring of the thyroid function in PSS patients is advisable.