High Serum TSH Levels Research Articles

Fatty liver largely explains associations of subclinical hypothyroidism with insulin resistance, metabolic syndrome, and subclinical coronary atherosclerosis.

The association of subclinical hypothyroidism (SCH) with insulin resistance, metabolic syndrome (MS), and coronary atherosclerosis is uncertain. To investigate the role of increased intrahepatic fat in the association of SCH with insulin resistance, MS, and coronary atherosclerosis. We conducted a cross-sectional study in a sample of 753 subjects (46% males) aged 35-70 years with no history of diabetes, renal, hepatic, thyroid, or coronary heart disease, and were participants of the Genetics of Atherosclerotic Disease study. SCH was defined as a high serum TSH level with normal free thyroxine concentration. Fatty liver (FL), coronary artery calcification (CAC), and abdominal visceral adipose tissue were assessed by computed tomography. Cross-sectional associations of SCH with and without FL, with MS, insulin resistance, and subclinical atherosclerosis defined as a CAC score >0, were examined in logistic regression models. SCH was observed in 17.7% of the population studied. The prevalence of FL was similar in both euthyroid and SCH subjects (31.8 vs 27.8%, P=0.371). SCH plus FL subjects were heavier and had more metabolic abnormalities compared with SCH plus normal liver subjects. In multivariate-adjusted logistic regression analyses, SCH plus FL was associated with MS (odds ratio (OR): 2.73, 95% CI: 1.26-5.92), insulin resistance (OR: 4.91, 95% CI: 1.63-14.75), and CAC score >0 (OR: 3.05, 95% CI: 1.20-7.76). SCH without FL showed no associations. SCH with FL is associated with increased odds of MS, insulin resistance, and CAC, independent of potential confounders.

Blood Thrombogenicity Is Independently Associated With Serum TSH Levels in Post–Non-ST Elevation Acute Coronary Syndrome

Higher serum TSH levels, both within the reference range and in those with subclinical hypothyroidism (SCH), have been associated with increased risk of atherosclerosis and cardiovascular (CV) events in a number of cross-sectional and longitudinal studies. Our objective was to evaluate blood thrombogenicity in patients post-non-ST elevation acute coronary syndrome (NSTE-ACS) in relation to their thyroid function. DESIGN, PATIENTS, AND OUTCOME MEASURE: At 1 week after troponin-positive NSTE-ACS, 70 patients who had been treated with optimal antiplatelet and secondary prevention therapy were studied. Patients with known thyroid disease or on medications affecting thyroid function were excluded. Blood thrombogenicity was assessed using the ex vivo Badimon perfusion chamber. Serum TSH was associated with higher thrombus burden (β = .30; P = .01) independent of other well-established CV risk factors. Patients with SCH (n = 12; 17%) had a higher thrombus burden than euthyroid individuals as evidenced by the area of the thrombus: mean (SD) 23 608 (10 498) vs 16 661 (10 902) μm(2)/mm (P = .02). However, this association was not evident when the analysis was limited to patients with serum TSH within the reference range. In addition, neither serum free T4 nor free T3 had any significant association with thrombus area. Serum TSH levels, particularly in the SCH range, are associated with higher thrombus burden despite optimal recommended secondary prevention therapy after NSTE-ACS. This may explain the higher CV risk seen in SCH patients. Future trials to assess the effect of individualized antithrombotic as well as thyroid hormone replacement therapy to reduce atherothrombotic risk in this population are needed.

A cross‐sectional study of the association between circulating TSH level and lipid profile in a large Spanish population

Some evidence suggests that high serum TSH levels are associated with an adverse lipid profile, but this association is not clear when plasma TSH is within the reference range. Nevertheless, these studies have never been conducted in Spain, a country with a strong adherence to the Mediterranean diet. The study aim was to analyse the association between blood TSH levels and circulating lipids in a large Spanish population and set up a TSH reference range in different age, gender and Body Mass Index (BMI) subpopulations from our cohort. Cross-sectional study on 20 783 subjects. We analysed circulating levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDLc), high-density lipoprotein cholesterol (HDLc) and triglycerides (TG) and compared them with TSH serum levels. Discriminant function analysis was used to determine the TSH cut-off level from where hyperlipidaemia developed. In individuals free of thyroid dysfunction, the mean and the 95% TSH (mU/l) reference limits were 2·20 and 0·72-4·43, respectively. We observed a sex-related difference in TSH concentration (men, 2·07 and 0·72-4·29; women, 2·29 and 0·72-4·49; P < 0·01). We also observed a weight-related difference in TSH concentration (BMI < 30 kg/m(2) , 2·16 and 0·72-4·39; BMI ≥ 30 kg/m(2) , 2·28 and 0·71-4·47; P < 0·01). TSH was positively associated with TC, TG and LDLc levels and negatively with HDLc. We found an association between TSH and lipids in that as TSH increased, the lipid profile became less favourable, even within the normal range. Additionally, TSH reference ranges varied according to gender, age and BMI.

Functional characterization of four novel PAX8 mutations causing congenital hypothyroidism: new evidence for haploinsufficiency as a disease mechanism

Individuals carrying a heterozygous inactivating PAX8 mutation are affected by congenital hypothyroidism (CH), although heterozygous Pax8 knockout mice are not. It has remained unclear whether CH in PAX8 mutation carriers is caused by haploinsufficiency or a dominant negative mechanism. To report clinical and molecular findings of four novel PAX8 mutations, including one early-truncating frameshift mutation. Four probands were CH patients. Two had family history of congenital or childhood hypothyroidism. Three probands were diagnosed in the frame of newborn screening for CH, while one had a negative result in screening but was diagnosed subsequently. Three had thyroid hypoplasia and one had a slightly small thyroid with low echogenicity. For these probands and their family members, we sequenced PAX8 using a standard PCR-based method. Pathogenicity of identified mutations was verified in vitro. We found four novel heterozygous PAX8 mutations in the four probands: L16P, F20S, D46SfsX24, and R133Q. Family studies showed four additional mutation carriers, who were confirmed to have high serum TSH levels. Expression experiments revealed that three mutations (L16P, F20S, and R133Q) had defects in target DNA binding, while D46fs had protein instability that was rescued by the proteasome inhibitor MG132. All four mutations had reduced transactivation on the thyroglobulin promoter, supporting that they were inactivating mutations. D46fs is the first PAX8 mutation with confirmed protein instability. Our clinical and in vitro findings together suggest that pure PAX8 haploinsufficiency can cause CH in humans.

Serum Thyroid-Stimulating Hormone Levels Are Associated with Blood Pressure in Children and Adolescents

It is currently unclear whether subclinical thyroid dysfunction is associated with blood pressure. Furthermore, data on the potential relation of thyroid function with blood pressure in children and adolescents are sparse. We investigated the association between serum TSH levels and blood pressure in a population-based study conducted in children aged 3-10 yr and adolescents aged 11-17 yr. Data from 6435 children and 5918 adolescents of the German Health Interview and Examination Survey for Children and Adolescents (KiGGS) were analyzed. Two readings of systolic and diastolic blood pressure were taken in a sitting position after 5 min of rest. Hypertension was defined by an increased systolic or an increased diastolic blood pressure using age-, sex-, and height-specific reference values from the KiGGS study. Serum TSH levels were measured with the electrochemiluminescence method. High and low serum TSH levels were defined according to age-specific reference limits for the assay. Continuous and categorized serum TSH levels were associated with hypertension by multivariable logistic regression. Serum TSH levels were significantly associated with hypertension in children (odds ratio=1.12; 95% confidence interval=1.00-1.25; P=0.045) and adolescents (odds ratio=1.19; 95% confidence interval=1.12-1.26; P<0.001). High serum TSH levels were positively associated with systolic and diastolic blood pressure, but not with hypertension in children and adolescents. There is a positive relationship between serum TSH levels and hypertension in children and adolescents, suggesting that subclinical hypothyroidism is associated with an increased risk of hypertension.

Association between the serum TSH concentration and thyroid cancer incidence

To investigate the association between serum TSH concentration and thyroid cancer incidence. Three hundred and thirty patients with thyroid tumors who underwent surgical treatment were included in this study (99 cases of malignancy and 231 cases of benign tumors). The data of their serum TSH level, gender, age, tumor type, and number of tumors detected by ultrasonic inspection were retrospectively analyzed, and their association with thyroid cancer incidence was explored. The proportion of thyroid cancer in the groups of younger than twenty years and older than seventy years were 63.0% and 58.3%, respectively, significantly higher than that in the group of age between 60 and 69 years (23.3%, P < 0.05). The incidence of thyroid cancer of the 81 male patients was 43.2%, significantly higher than that in the 249 female patients (25.7%, P = 0.003). The incidence of thyroid cancer in the 112 patients with single nodule was 42.0%, significantly higher than that in the 218 patients with multiple nodules (23.9%, P < 0.001). In the groups with TSH level lower than 0.28 mIU/L and higher than 4.20 mIU/L, the incidence of thyroid cancer were 54.6% and 50.0%, respectively, significantly higher than that in the group with TSH level between 0.28 and 1.44 mIU/L (16.1%, P < 0.05). The proportion of patients with thyroid cancer was also increased with the increasing serum TSH level in the normal range (P < 0.001). High serum TSH level (OR = 1.465, P = 0.014), male (OR = 1.964, P = 0.016) and a single thyroid nodule (OR = 2.090, P = 0.006) are independent risk factors of thyroid cancer. The high serum TSH level, male, single thyroid nodule are factors leading to a high incidence of thyroid cancer.

Increased fetal abortion rate in autoimmune thyroid disease is related to circulating TPO autoantibodies in an autoimmune thyroiditis animal model

To determine the fertility and abortion rates in a mouse model of autoimmune thyroiditis and its relationship with circulating anti-thyroid peroxidase (TPO) antibody. Experimental animal study. University research laboratory. C57bl/6 mice. Female C57bl/6 mice immunized with recombinant mouse TPO (rmTPO) in complete Freund adjuvant (CFA) or glutathione-S-transferase (GST-CFA) were allowed to mate. The pregnant mice were killed on day 14 of pregnancy for assessment of fetal development. The effects of TPO antibody on preimplantation embryo development and implantation rate were also studied. Litter size, resorption rate, preimplantation embryo development, and implantation rate. All of the mice immunized with rmTPO-CFA possessed anti-TPO antibody. They had reduced litter size and increased incidence of resorbed fetus compared with the control. Higher serum TSH levels, but not T(4) levels, were demonstrated after rmTPO-CFA immunization. Anti-TPO antibody bound to preimplantation embryos. Treatment of the embryos with the antibody marginally decreased the formation of 3/4-cell embryos but had no effect on the subsequent development and implantation compared with the nonimmune control sera. Autoimmune thyroiditis is associated with reduced fertility and higher incidence of fetal loss. The anti-TPO antibody may affect post-implantation embryo development, leading to fetal loss.

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.

Are serum thyrotropin levels within the reference range associated with endothelial function?

High serum thyrotropin (TSH) levels within the reference range might be associated with an increased cardiovascular risk. In the present study, we investigated the association between serum TSH levels and flow-mediated dilation (FMD) as a measure of endothelial dysfunction. The study population comprised 1364 subjects (670 women) aged 25-85 years with serum TSH levels between 0.25 and 2.12 mIU/L recruited from 5-year follow-up of the Study of Health in Pomerania. No interventions were performed. Measurements of FMD and nitrate-mediated dilation (NMD) were performed in the supine position using standardized ultrasound techniques. FMD and NMD values below the median of each distribution were considered decreased. Analyses adjusted for age, sex, smoking, and systolic and diastolic blood pressure revealed a non-significant inverse trend between serum TSH levels and FMD (P = 0.130). Subjects with serum TSH levels above the highest quartile had lower median FMD values relative to subjects with serum TSH levels below the lowest quartile (4.86 vs. 5.43%, P < 0.05). A linear inverse trend between serum TSH levels and decreased FMD barely missed statistical significance (P = 0.138). Subjects with high serum TSH levels had higher odds of decreased FMD relative to subjects with low serum TSH levels (odds ratio 1.42; 95% confidence interval 1.02; 1.96; P < 0.05). These associations were more pronounced in men than in women. There were no such associations for NMD. Serum TSH levels within the upper reference range are associated with impaired endothelial function. Our findings contribute to the discussion on whether the upper TSH reference limit should be redefined.

Serum thyrotropin levels predict all-cause and circulatory mortality in patients with invasively treated coronary artery disease

The aim of the present study was to analyze the relation of low or high serum thyrotropin (TSH) with mortality in patients with invasively treated coronary artery disease. We followed-up 942 patients who underwent coronary angioplasties or coronary artery bypass graft surgery over a mean follow-up period of 6.4 ± 1.6 years. The study population was divided into three groups using the reference limits of serum TSH (0.25–2.12 mIU/l) as cut-offs. There were 118 patients (12.5%) with low and 125 patients (13.3%) with high serum TSH. One hundred and seventy-four subjects (18.5%) deceased during follow-up. Multivariable analyses revealed that both subjects with low and high serum TSH had a lower all-cause and circulatory mortality than subjects with serum TSH within the reference range. We conclude that low and high serum TSH levels are associated with a reduced all-cause and circulatory mortality in patients with coronary artery disease.

Valores inesperadamente elevados de TSH: a presença de formas de alto peso molecular ("macro TSH") deve ser investigada

The laboratory methods usually employed for the measurement of serum TSH present sensitivity and specificity levels, both analytical and clinical, are highly satisfactory. Additionally, the methodologies are quite robust, so that false-positive and false-negative results are rare and unexpected. In this paper we describe two individuals quoted as euthyroid clinically, with no reference to autoimmune diseases, and no reference to the use of exogenous TSH, that presented with normal to extremely high serum TSH levels, depending on the method employed for analysis. In the three tested methods, serial dilution showed that the real TSH levels were between 250 and 300 mUI/L. In both cases the increment in TSH levels were due to the presence of TSH-binding proteins, forming high molecular weight complexes ("macro TSH"), well characterized by gel filtration chromatography on Superdex S-200 column. In one of the patients the binding protein was characterized as being IgG by protein-G binding study. In the other case, protein-G binding as well as anti-IgM binding failed to characterize the protein. These two cases call attention to the importance of the clinical-laboratory correlation and suggest the need that the presence of "macro TSH" must be investigated in patients with unexpectedly high TSH values.

Thyroid-Specific Enhancer-Binding Protein/NKX2.1 Is Required for the Maintenance of Ordered Architecture and Function of the Differentiated Thyroid

Thyroid-specific enhancer-binding protein (T/ebp)/Nkx2.1-null mouse thyroids degenerate by embryonic day (E) 12-13 through apoptosis whereas T/ebp/Nkx2.1-heterogyzgous mice exhibit hypothyroidism with elevated TSH levels. To understand the role of T/ebp/Nkx2.1 in the adult thyroid, a thyroid follicular cell-specific conditional knockout (KO) mouse line, T/ebp(fl/fl);TPO-Cre, was established that expresses Cre recombinase under the human thyroid peroxidase (TPO) gene promoter. These mice appeared to be healthy and exhibited loss of T/ebp/Nkx2.1 expression in many, but not all, thyroid follicular cells as determined by immunohistochemistry and real-time PCR, thus presenting a T/ebp-thyroid-conditional hypomorphic mice. Detailed analysis of the thyroids from T/ebp(fl/fl), T/ebp(fl/fl);TPO-Cre, and T/ebp(fl/ko) mice, where the latter mouse line is derived from crosses with the original T/ebp/Nkx2.1-heterozygous mice, revealed that T/ebp(fl/fl);TPO-Cre mice can be classified into two groups with different phenotypes: one having atrophic/degenerative thyroid follicles with frequent presence of adenomas and extremely high serum TSH levels, and the other having an altered thyroid structure with reduced numbers of extraordinary dilated follicles consisting of excessive numbers of follicular cells as compared with those usually found in the normal thyroid. The latter phenotype was also observed in aged T/ebp(fl/ko) mouse thyroids. In vitro three-dimensional thyroid primary cultures using thyroids from T/ebp(fl/fl);TPO-Cre, T/ebp(fl/ko), and T/ebp(fl/fl) mice, and the latter treated with recombinant adenovirus with and without Cre expression, demonstrated that only cells from T/ebp(fl/fl) mice without adeno-Cre treatment formed follicular structures. Taken together, these results suggest that T/ebp/Nkx2.1 is required for maintenance of the normal architecture and function of differentiated thyroids.

Inhibition of pituitary type 2 deiodinase by reverse triiodothyronine does not alter thyroxine-induced inhibition of thyrotropin secretion in hypothyroid rats

Intrapituitary triiodothyronine (T3) production plays a pivotal role in the control of TSH secretion. Its production is increased in the presence of decreased serum thyroxine (T4) concentrations and the enzyme responsible, deiodinase type 2 (D2), is highest in hypothyroidism. In order to document the role of this enzyme in adult rats we developed an experimental model that inhibited this enzyme using the specific inhibitor, reverse T3 (rT3). Hypothyroidism was induced with propylthiouracil (PTU; 0.025 g/l in drinking water) which in addition blocked deiodinase type 1 (D1) activity, responsible for the rapid clearance of rT3 in vivo. During the last 7 days of the experiment, the hypothyroid rats were injected (s.c.) for 4 days with 0.4 or 0.8 nmol T4 per 100 g body weight (bw) per day. For the last 3 days, the same amount of T4 was infused via s.c. minipumps. In additional groups, 25 nmol rT3/100 g bw per day were added to the 3-day infusion of T4. Infusion of 0.4 nmol T4/100 g bw per day did not affect the high serum TSH levels, 0.8 nmol T4/100 g bw per day decreased them to 57% of the hypothyroid values. The infusions of rT3 inhibited D2 activity in all organs where it was measured: the pituitary, brain cortex and brown adipose tissue (BAT). In the pituitary, the activity was 27%, to less than 15% of the activity in hypothyroidism. Despite that, serum TSH levels did not increase, serum T4 concentrations did not change and the changes in serum T3 were minimal. We conclude that in partly hypothyroid rats, a 3-day inhibition of D2 activity, without concomitant change in serum T4 and minimal changes in serum T3 levels, is not able to upregulate TSH secretion and we postulate that this may be a reflection of absent or only minimal changes in circulating T3 concentrations.

Association between thyroid function and gallstone disease

To investigate those associations using data of the population-based Study of Health in Pomerania. A study population of 3 749 residents aged 20-79 years without previously diagnosed thyroid disease was available for analyses. Serum TSH was used to assess thyroid function. Cholelithiasis was defined by either a prior history of cholecystectomy or the presence of gallstones on ultrasound. Logistic regression was performed to analyze independent associations between thyroid function and cholelithiasis. There were 385 persons (10.3%) with low (<0.3 mIU/L), 3 321 persons (88.6%) with normal and 43 persons (1.2%) with high serum TSH levels (>3 mIU/L). The proportion of cholelithiasis among males and females was 14.4% and 25.3%, respectively. Among males, there was an independent relation between high serum TSH and cholelithiasis (OR 3.77; 95%-CI 1.06-13.41; P<0.05). Also among males, there was a tendency towards an elevated risk of cholelithiasis in persons with low serum TSH (OR 1.40; 95%-CI 0.96-2.02; P = 0.07). In the female population, no such relation was identified. There is an association between thyroid and gallstone disease with a gender-specific relation between hypothyroidism and cholelithiasis.

High serum TSH levels are associated with depression in the elderly

In order to investigate the association between elevated serum TSH levels and depression in the elderly, we conducted a population-based study of 451 over 60-year-old outpatients of a general University Hospital. Patients were divided into Group I (GI) (248 individuals) with high serum TSH levels, but otherwise no important condition or disease, and Group II (GII) (203 patients) with no previous diagnosis of thyroid or mood disease, referred to the hospital because of nonthyroidal severe diseases. All patients were clinically examined and classified according to DMS-IV for mood disturbance and had serum TSH, free T4 levels and antithyroid antibodies measured. High serum TSH levels (11.6±14.8 mU/l) were observed in 65/203 (32%) patients of GII. Among these patients, 42/65 (65%) had normal free T4 concentrations (1.23±0.98 ng/dl), no clinical manifestation of hypothyroidism and thus were considered to present subclinical hypothyroidism. Depression was observed in 24 cases from GI (9.7%) and 29 from GII (14.3%) and was frequent in the subclinical hypothyroid patients (49%). Our results suggest that mood disturbances are frequent in the elderly with elevated serum TSH levels, but they do not differ in the primary hypothyroid and the nonthyroidal sick patients.

Congenital hypothyroidism in a child with unsuspected familial dysalbuminemic hyperthyroxinemia caused by a mutation (R218H) in the human albumin gene

We found familial dysalbuminemic hyperthyroxinemia (FDH) in a 5-month-old boy with congenital hypothyroidism (CH) who had a blood thyrotropin (TSH) level of 479 mU/L but normal total serum thyroxine (T 4) and higher than normal total triiodothyronine (T 3) levels. Thyroid hormone substitution began at 5 weeks of age when T 4 and T 3 concentrations were below normal. Until the age of 5 months, treatment with levothyroxine was suboptimal on the basis of high serum TSH levels despite above-normal T 4 levels. FDH was confirmed by isoelectric focusing and testing of other family members. DNA analysis of the patient revealed R218H, a mutation in the serum albumin gene associated with FDH, which was also present in the patient's euthyroid father and brother. Thyroid scans, serum thyroglobulin measurements, and free T 4 measurements using equilibrium dialysis or 2-step immunoassay methods can identify thyroid hormone-binding protein defects and simplify the diagnosis and treatment of infants with CH. (J Pediatr 2001;139:887–91)

The hypothyroidism in an inbred kindred with congenital thyroid hormone and glucocorticoid deficiency is due to a mutation producing a truncated thyrotropin receptor.

Growth and function of the thyroid and adrenal glands are maintained and controlled by thyrotropin (TSH) and adrenocorticotrophic hormone (ACTH), respectively. The action of these trophic hormones requires the presence of functional TSH and ACTH receptors. We describe a large inbred Bedouin kindred in which profound congenital hypothyroidism and hypoadrenocortisolism occurred alone or together in eight family members belonging to four nuclear families. The high serum TSH and ACTH levels in the presence of normal or hypoplastic thyroid glands and low glucocorticoid, but not mineralocorticoid concentrations, are characteristic of resistance to TSH and ACTH. Linkage analysis, using specific polymorphic markers, excluded the involvement of the ACTH receptor but not thyrotropin receptor (TSHR). A novel point mutation was identified in exon 10 of the TSHR that replaces the normal cytosine in nucleotide 2024 with a thymidine. As a result the normal arginine in codon 609 (CGA) is replaced with a stop codon (TGA). This mutation produces a truncated TSHR lacking the third intracellular and extracellular loops, the sixth and seventh transmembrane segments, and the intracytoplasmic tail. The presence of hypothyroidism did not affect the timing, severity, and manner of clinical manifestation of hypoadrenocortisolism.

Recurrent T354P mutation of the Na+/I- symporter in patients with iodide transport defect.

Iodide transport defect (ITD) is a rare disorder causing congenital hypothyroidism. We previously reported that homozygous T354P mutation in the sodium/iodide symporter (NIS) gene caused ITD. To clarify the prevalence of this mutation, artificial substitution introducing PCR followed by restriction enzyme analysis was developed as a rapid screening method to detect the T354P mutation. Three apparently unrelated families with ITD, one patient with low thyroidal 99mTc pertechnetate (99mTcO4-) uptake and 52 healthy controls (104 alleles) were analyzed for this mutation. All families with ITD harbored the mutation, suggesting that T354P is a recurrent mutation and a major cause of ITD. This was not a widespread mutation, because it was not detected in the 52 unrelated normal controls. Because two cases with homozygous T354P mutation developed multinodular goiters within their second decade of life though they had been maintained in euthyroid state, homozygous T354P mutation alone and/or low intrathyroidal iodide and high serum TSH level in early life might account for tumorigenesis. The patient with low thyroidal 99mTcO4- uptake did not harbor the T354P mutation. Because familial hypocalciuric hypercalcemia was also present in this family, a possibility of the combined abnormality of TSH receptor and calcium functions, which includes an abnormality around the G protein, may be examined further.

Effect of Primary Hypothyroidism on Fetal Mouse Lung Surfactant Protein A, B and C, and Thyroid Transcription Factor-1 Protein and Gene Expression.† 1456

Primary hypothyroidism in the Hyt/Hyt mice is due to a point mutation(Pro-556-Leu) in the β subunit of the TSH receptor of the thyroid gland and is transmitted as an autosomal recessive trait. Fetal hypothyroidism is associated with delayed fetal lung ultrastructural maturation (Ped. Res. 36:380:94). Surfactant proteins (SP-A, B & C) & Thyroid Transcription Factor-1 (TTF-1) play an important role in fetal lung surfactant function and type II cell differentiation, but the effect of primary hypothyroidism on the developmental expression of fetal lung SP-A, SP-B, SP-C or TTF-1 has not been investigated. Hyt/Hyt mice identified by high serum TSH and low free T4 levels were made euthyroid by supplemental T3. The mice were then bred to carry Hyt/Hyt pups. Balb-c euthyroid mice served as controls. All mice were killed on d 18 of gestation (term ≈20 d, vaginal plug = d 1 of pregnancy). Fetal lung immunostaining for SP-A, SP-B, SP-C and TTF-1 was performed and gene expression of these proteins was determined by Northern blot analysis. The TTF-1 immunoreactivity was nuclear in localization and confined to the type II cells, while staining for SP-A, SP-B and SP-C was cytoplasmic and present in type II cells as well as within the alveolar lumen. The intensity and distribution of the immunoreactivity scored on a scale of 0 to 3, for SP-A, SP-B and SP-C and TTF-1 (n=5) was markedly decreased in the Hyt/Hyt fetal lungs when compared to the controls (n=5). While gene expression for SP-C(≈0.8 kb) and TTF-1 (≈2.3 kb) was significantly decreased in the hyt/hyt mice, the gene expression for SP-B (≈0.9 kb) was similar in both groups. CON: Primary hypothyroidism is associated with a delay in the developmental expression of fetal lung SP-A, SP-B, SP-C and TTF-1 protein, and a differential expression for SP-B, SP-C and TTF-1 genes. These findings may explain a higher incidence of RDS in human neonates with hypothyroidism(NIH-HL 52839).

Time course observation of thyroid proliferative lesions and serum TSH levels in rats treated with thiourea after DHPN initiation

Time course changes in serum TSH and quantitative data for thyroid proliferative lesions in male F344 rats administered N-bis(2-hydroxypropyl)nitrosamine (DHPN: 2000 mg/kg body weight, single s.c. injection) followed by 0.1% thiourea (TU), were assessed at weeks 1, 2, 4, 8, 12 and 16 of treatment. The serum T4 level in the TU group was markedly decreased at week 1 and remained significantly lowered throughout the experiment. Serum TSH levels, in contrast, were elevated up to a peak at around week 4 with a return to the normal range at week 12. Thyroid weights in the TU group were increased significantly in a treatment period-dependent manner. Histopathologically, marked hypertrophy of thyroid follicular cells occurred at the early stage of TU treatment. Proliferative lesions, such as hyperplasia and adenomas, occurred from weeks 2 and 4, respectively, and increased with the later treatment period. The cell proliferative activity of follicular cells, assessed by BrdU incorporation, was high until week 2, but then returned to normal. The initially appearing hyperplasias and adenomas were characterized by marked proliferation but this also greatly decreased at later stages when TSH was no longer elevated. The results of our study thus suggest that a high serum TSH level plays an important role in the early phase of thyroid tumorigenesis and 8 weeks treatment with test substances is sufficient for detection of thyroid tumor promoter potential in two-stage thyroid carcinogenesis models.