Relationship of Type 2 diabetes to the prevalence, incidence and progression of age-related hearing loss.

AIMS: Type 2 diabetes and associated microvascular abnormalities are postulated to affect hearing. Our study reports on the relationship between Type 2 diabetes and the prevalence, 5-year incidence and progression of hearing impairment in a representative, older, Australian population. METHODS: The Blue Mountains Hearing Study is a population-based survey of age-related hearing loss conducted in a defined suburban area, west of Sydney. Hearing loss was defined as the pure-tone average of frequencies 0.5, 1.0, 2.0 and 4.0 kHz > 25 decibels hearing level (dB HL) in the better ear (bilateral hearing loss). Type 2 diabetes was defined from reported physician-diagnosed diabetes or fasting blood glucose > or = 7.0 mmol/l. RESULTS: Age-related hearing loss was present in 50.0% of diabetic participants (n = 210) compared with 38.2% of non-diabetic participants (n = 1648), odds ratio (OR) 1.55 [95% confidence interval (CI) 1.11-2.17], after adjusting for multiple risk factors. A relationship of diabetes duration with hearing loss was also demonstrated. After 5 years, incident hearing loss occurred in 18.7% of participants with, and 18.0% of those without diabetes, adjusted OR 1.01 (CI 0.54-1.91). Progression of existing hearing loss (> 5 dB HL), however, was significantly greater in participants with newly diagnosed diabetes (69.6%) than in those without diabetes (47.8%) over this period, adjusted OR 2.71 (CI 1.07-6.86). CONCLUSIONS: Type 2 diabetes was associated with prevalent, but not incident hearing loss in this older population. Accelerated hearing loss progression over 5 years was more than doubled in persons newly diagnosed with diabetes. These data explore further reported links between Type 2 diabetes and age-related hearing loss.

Normal thiopurine methyltransferase phenotype testing in a Crohn disease patient with azathioprine induced myelosuppression.

Severe cytopenias in patients with autoimmune conditions treated with azathioprine are well-recognized. Thiopurine methyltransferase (TPMT) enzymatic activity is subject to individual and ethnic variability. Patients with low TPMT activity (poor metabolizers) are at high risk of developing severe and potentially fatal haematopoietic toxicity. Studies have shown that essentially all TPMT-deficient patients will develop haematopoietic toxicity on administration of conventional thiopurine dosages (6-mercaptopurine, azathioprine). Therefore, screening for TPMT polymorphisms in patients before prescribing thiopurine drugs has been proposed. However, despite normal in vitro enzymatic activity, cytopenia may still occur in vivo. This is the case report of an Asian patient with Crohn disease harbouring a rare TPMT mutation on DNA sequencing, who developed neutropenic sepsis and anaemia after a flare of Crohn disease. The report illustrates the importance of monitoring for cytopenia in the setting of active inflammatory disease despite prior normal phenotyping, the role of predictive pharmacogenetics and the limitations of TPMT phenotype assays that may result in misclassification of at-risk patients.

Somatostatin-14 and its analog octreotide exert a cytostatic effect on GH3 rat pituitary tumor cell proliferation via a transient G0/G1 cell cycle block.

Somatostatin (SRIF) and its analogs exert potent inhibitory effects on hormonal hypersecretion. In addition, they have been demonstrated to inhibit the proliferation of various cell lines as well as the growth of some endocrine tumors in vivo. To evaluate the action of SRIF and its analog octreotide on the proliferation and cell cycle kinetics of endocrine cells, we investigated their effect on GH3 rat pituitary tumor cells, a GH-producing cell line. Using flow cytometric DNA analysis with propidium iodide staining, we found that octreotide inhibits the proliferation of synchronized GH3 cells, achieving a maximal reduction, compared to controls, of 19.4 +/- 5.3% and 22.4 +/- 5.1% with 100 ng/ml and 1000 ng/ml octreotide, respectively (P < 0.05). This effect was demonstrated to be due to a block in progression from the G0/G1 phase to the S phase of the cell cycle. This was most evident after 24 h of exposure to 100 ng/ml octreotide, at which time there was a 7.1 +/- 1.4% increase in cells in G0/G1 (P < 0.01) and a 6.6 +/- 1.3% decrease in cells in S phase (P < 0.01). However, unless octreotide was replenished, this effect was transient and overcome by 36-48 h. No apoptosis was seen, and trypan blue studies confirmed that cell death by necrosis did not occur. A single exposure to native SRIF-14 had little effect, but a G0/G1 cell cycle block and inhibition of proliferation were seen if SRIF was regularly replenished. We conclude that SRIF and octreotide exert a cytostatic effect on GH3 cells by causing a partial G0/G1 cell cycle block. These findings suggest that the actions of SRIF and octreotide occur through signal transduction pathways that act predominantly on downstream regulators.

Detection of extended distribution of beta2-thyroid hormone receptor messenger ribonucleic acid (RNA) in adult rat brain using complementary RNA in situ hybridization histochemistry.

In situ hybridization histochemistry using a complementary RNA probe, directed at the entire length of the thyroid hormone receptor beta2 (TRbeta2)-specific region (-56 to 495 bp), was used to evaluate expression of TRbeta2 messenger RNA (mRNA) in coronal sections of adult rat brain. An extended distribution and intense expression of TRbeta2 mRNA was found in several regions of rat brain, including regions where TRbeta2 mRNA had not been previously identified using PCR or in situ hybridization histochemistry. These areas included hippocampus (dentate gyrus and C1, -2, and -3), cerebral cortex (predominantly layer 3), arcuate nucleus, median eminence, medial geniculate nucleus, tegmental bundle, medial and lateral lemniscus, Purkinje layer of the cerebellum, and several brain stem nuclei. In conclusion, we have developed a highly sensitive and specific method to demonstrate TRbeta2 mRNA expression in adult rat brain. The present findings are in agreement with immunoreactive TRbeta2 studies of rat brain and argue against the presence of an unidentified T3-binding protein to explain the previous discordant results of TRbeta2 mRNA and protein studies. In addition, the specificity of distribution of TR beta2 mRNA to certain brain nuclei, particularly those involved in hearing, implies a specific functional role of this receptor subtype and provides a physiological basis to understand the effects of hypothyroidism on brain development.

Methimazole inhibits FRTL5 thyroid cell proliferation by inducing S-phase arrest of the cell cycle.

Previous studies, using tritiated thymidine uptake assays, had indicated a nil or stimulatory effect of methimazole (MMI) on thyroid cell proliferation. Whilst examining cell cycle kinetics of FRTL5 thyrocytes, we observed an inhibitory effect of MMI on thyroid cell proliferation. To further examine this observation, FRTL5 cells whilst in log phase proliferation were exposed to media containing either 6H or MMI in 6H. Cell number and cell cycle kinetics were examined using flow cytometric DNA analysis every 24 hrs for 96 hrs. We found that MMI inhibited cell proliferation (as assessed by cell number) throughout the experimental period. Cell cycle analysis revealed a persistent arrest of cells in S phase. Concomitantly, there was a fall in the proportion of cells in both G0G1 and G2M phases, in keeping with cell cycle arrest in S phase. Taken in isolation, the finding of a high proportion of cells in S phase would suggest stimulation of cell proliferation, consistent with the findings of previous studies which used tritiated thymidine uptake assays to assess cell proliferation. However, the absence of a concomitant increase in total cell number renders this argument invalid and argues for a specific effect of MMI on the cell cycle. This study demonstrates a hitherto unrecognised inhibitory action of MMI on FRTL5 thyroid cell proliferation which has implications in understanding the broader effects of MMI on thyroid cell physiology. Additionally, this study highlights the dangers of using tritiated thymidine uptake measures as the sole indicator of mitogenic activity.

Evidence that the inhibitory effects of iodide on thyroid cell proliferation are due to arrest of the cell cycle at G0G1 and G2M phases.

The thyroid gland is unique in its ability to respond to ambient levels of iodine to autoregulate thyroid function and, possibly, thyroid cell proliferation. Although the inhibitory effects of iodide on thyroid cell proliferation have been previously reported, the exact mechanism and site of action of iodide on cellular proliferation events are poorly understood. Our initial experiments established the optimal cell plating density and timing to achieve exponential cell growth of FRTL5 thyroid cells, and subsequent studies using flow cytometric DNA analysis established the normal cell cycle kinetics of FRTL5 thyroid cell proliferation. FRTL5 cells were then exposed to graded concentrations of sodium iodide to establish whether the inhibitory effects of iodide are mediated through specific cell cycle events. We observed that increasing concentrations of iodide inhibited FRTL5 thyroid cell proliferation. Analysis of the cell cycle revealed two specific effects of iodide on cell cycle kinetics. The first was an arrest of cells in G0G1, evidenced by an accumulation of cells in this phase and a concomitant reduction in the percentage of cells in the S-phase. The second was an arrest of cells in the G2M phase of the cycle. G0G1 and G2M arrest occurred within 24 h and then reached a plateau. Iodide exposure did not increase the number of cells undergoing necrosis. The addition of methimazole at two concentrations (0.2 and 2 mM) to cells exposed to 100 mM NaI prevented the accumulation of cells in G2M, but did not abolish the accumulation of cells in G0G1 or the reduction in cell number. These results indicate that the inhibitory effects of iodide on FRTL5 thyroid cell proliferation are mediated by its action at two critical regulating points of the cell cycle, G0G1 and G2M. It appears that organified iodine may mediate the cell cycle arrest in the G2M phase, whereas inorganic iodide may be responsible for the inhibitory effects at G0G1.

Growth hormone does not increase thyroid size in the absence of thyrotropin: a study in adults with hypopituitarism.

Goiter is a frequent clinical finding in patients with acromegaly, an effect mediated by chronically elevated insulin-like growth factor I (IGF-I) levels. It is unclear, however, whether the presence of TSH is a prerequisite for the growth-promoting actions of IGF-I on the human thyroid. We, therefore, studied a group of subjects with hypopituitarism, who were deficient in both TSH and GH, examining the effects of GH replacement therapy on thyroid size and function. GH replacement was initiated in 14 subjects with hypopituitarism. After 6 months of recombinant human GH therapy at 0.25 IU/ kg week, IGF-I levels increased from 11.5 +/- 6.0 to 32.4 +/- 15.4 nmol/L (P = 0.002). Thyroid volume, as determined by ultrasound, did not change significantly over this period. Similarly, there was no change in thyroglobulin levels after treatment with GH, but there was a decrease in the free T4/free T3 ratio (P = 0.043). Pretreatment thyroid size in subjects with hypopituitarism was also compared to that in a group of age- and sex-matched controls. The size of thyroid glands in the hypopituitarism group was smaller than that in controls (P = 0.015). We found that GH therapy did not increase thyroid size in patients with hypopituitarism. From these data we conclude that in vivo, IGF-I does not independently stimulate thyroid growth, but promotes thyroid cell proliferation by potentiating the mitogenic action of TSH.

Growth hormone treatment increases cytochrome P450-mediated antipyrine clearance in man.

We used the antipyrine clearance test (APC) to examine the effect of growth hormone (GH) therapy on hepatic cytochrome P450 (CYP) enzyme activity. Eleven GH deficient adults were randomized to receive GH or placebo for 6 months, all subjects subsequently received GH. Before treatment, APC was below the normal range in six subjects. We found an increase in APC in the subjects randomized to receive GH compared to those on placebo (median change +0.14 ml/min/kg [range + 0.04 to + 0.20]vs -0.04 ml/min/kg [range -0.07 to + 0.04], p = 0.011). The stimulatory effect of GH on drug metabolism was confirmed by the data for 3 months GH treatment in all 11 subjects, with APC increasing from 0.33 ml/min/kg (range 0.22 to 0.69) to 0.50 ml/min/kg (range 0.27 to 0.83), p = 0.018). These data indicate that GH modulates hepatic CYP activity. This has important clinical implications, as the hepatic metabolism of drugs and hormones may be altered in patients undergoing GH therapy.

Supplementary iodine fails to reverse hypothyroidism in adolescents and adults with endemic cretinism.

The efficacy of supplemental iodine in correcting hypothyroidism in adults and older children with endemic myxedematous cretinism is not known. To investigate this issue we administered im iodized oil (1.5 mL) to 28 hypothyroid endemic cretins (TSH, greater than 5 mIU/L) from western China, aged 14-52 yr (mean = 29 SD = 11 yr). Clinical examination, intelligence testing (Hiskey Nebraska Test of Learning Aptitude and the Griffiths Mental Development Scales), and thyroid function tests were performed before and 6 months after iodine supplementation. We found that signs of thyroid hormone deficiency, dwarfism, and delayed sexual maturity persisted after iodine supplementation. Further, mental disability and other clinical features of neurological damage were not altered by treatment. The mean serum concentration of total T4 before treatment was 75 nmol/L (SD = 40) and fell after iodized oil administration to 56 nmol/L (SD = 29; P less than 0.001). Mean serum levels of TSH before and after iodine showed a paradoxical fall [85 mIU/L (SD = 102) and 46 mIU/L (SD = 46), respectively]. Serum TSH levels decreased into the normal range (less than 5 mIU/L) in only 1 of 28 patients (4%). We conclude that iodine supplementation does not reverse thyroid hormone deficiency or its sequelae in adolescents and adults with endemic myxedematous cretinism. Iodized oil in this age group of patients with endemic cretinism does not appear to be beneficial and should be used with caution.

A comparative study of neurological and myxedematous endemic cretinism in western China.

Endemic cretinism occurs in areas of severe iodine deficiency and is manifested by two major clinical patterns, myxedematous and neurological. The relationship between these types and the factors responsible for the clinical variability are not clear. We examined 69 endemic cretins, aged 4-52 yr, categorized clinically at the beginning of the study into the three traditional types of endemic cretins, myxedematous (n = 25), neurological (n = 15), and the mixed form (n = 29), from a previously unreported endemia in Qinghai Province, China. These patients underwent detailed endocrine and neurological examination, including intelligence assessment using the Hiskey-Nebraska Test of Learning Aptitude or the Griffiths Mental Development Scales, audiometry (in a subset of 37 patients); thyroid function testing and thyroid ultrasonography; and radiology of the skull, hand, and hip. We found that categorization of the cretins into the conventional types did not reflect the pathophysiology of the condition, since an identical pattern and intensity of neurological, intellectual, and audiometric deficits were common to and equally present in all three types of endemic cretins regardless of their thyroid function. Gait disorder (in 99%) and pyramidal signs such as patellar hyper-reflexia (in 91%) were the most common neurological abnormalities. There was no difference in mean intelligence test scores among the three groups [overall mean intelligence score (Hiskey or Griffiths tests), 28.8 +/- 12.8 (SD)]. The differing clinical manifestations of cretinism could be explained by the length and severity of thyroid hormone deficiency. Myxedematous cretins were severely thyroid hormone deficient, and as a result sexually immature, dwarfed, and had retarded skeletal maturity. They had clinical and sonographic thyroid atrophy, rather than goiter. Although neurological cretins were euthyroid, linear growth arrest lines (demonstrated radiologically) in the long bones of these cretins suggested previous hypothyroidism. Furthermore, all cretins were growth retarded when compared with peers of similar age and race. Our data therefore suggest that the different clinical types of endemic cretinism are in fact the same disorder phenotypically modified by the length and severity of postnatal hypothyroidism. The neurological manifestations are interpreted as reflecting the effects of maternal and fetal hypothyroxinemia, secondary to severe iodine deficiency, on the developing nervous system.

Thyroid dysfunction following radiotherapy for head and neck cancer.

PURPOSE: To determine the frequency of hypothyroidism (both subclinical and clinical) following external beam radiotherapy to the whole of the thyroid gland in the treatment of squamous cell cancers of the head and neck. METHODS AND MATERIALS: One hundred and four patients who had completed radiotherapy 30 days to 5 years earlier (84 patients) or who were scheduled for radiotherapy (20 patients) had a single measurement of serum-free thyroxine and thyroid stimulating hormone levels between August 1991 and May 1992. RESULTS: None of the 20 patients assessed prior to treatment showed thyroid dysfunction. Twenty of 84 (23.8%) previously treated patients had subclinical (9.5%) or clinical (14.3%) hypothyroidism. By 5 years, up to 40% of patients may become hypothyroid. Thyroid underactivity was significantly more common in patients having both laryngectomy (including hemi-thyroidectomy) and radiotherapy compared to radiotherapy alone (p < 0.001). Hypothyroidism had not been suspected clinically in any patient tested. CONCLUSION: In view of the frequency and potential morbidity of this complication, thyroid function testing should become a routine part of posttreatment follow-up for these patients.

Amiodarone compared with iodine exhibits a potent and persistent inhibitory effect on TSH-stimulated cAMP production in vitro: a possible mechanism to explain amiodarone-induced hypothyroidism.

Amiodarone (AMD) is a powerful anti-arrhythmic drug used for the treatment of a wide variety of cardiac arrhythmias and its most striking feature is its high iodine content. Thyroid dysfunction is a limiting side-effect of the drug and both AMD-induced hypothyroidism (AIH) and AMD-induced thyrotoxicosis (AIT) are reported. To examine the hypothesis that altered bioavailability of iodine is a contributing event in the pathogenesis of AIH, we compared the effects of AMD and inorganic iodine in vitro on events involved in the process of thyroid autoregulation. FRTL-5 cells and JP26 CHO cells (transfected with the human TSH receptor) were exposed to AMD or NaI in the presence of TSH, and cAMP production was measured as an indicator of cellular function. Forskolin and cholera toxin were also used to determine the possible target sites of AMD and iodide. Our results indicated that there was a difference between the effects of AMD versus those of physiological doses of iodide. The inhibitory effects of AMD occurred at lower concentrations of iodide than those seen in the NaI-treated cells. The effects of AMD were irreversible indicating a possible persistence of the Wolff-Chaikoff effect due to a constant high intracellular iodide level. The inhibitory effects of AMD (also seen at supraphysiological doses of iodide) were partially overcome by forskolin but not by cholera toxin indicating an effect on TSH receptor interactions with the other signal transduction elements such as G proteins and adenylate cyclase. The persistence of the Wolff-Chaikoff effect through loss of autoregulation may be a mechanism of the observed hypothyroidism in some patients taking AMD. The combined effects of the constant release of iodide together with the drug toxicity may be the mechanism for the observed effects.

Thyroid ultrasound is the best prevalence indicator for assessment of iodine deficiency disorders: a study in rural/tribal schoolchildren from Gujarat (Western India).

OBJECTIVES: (i) To assess the severity of iodine deficiency disorders (IDD), (ii) to determine the aetiology of IDD in Gujarat, (iii) to identify the best prevalence indicator of IDD, and (iv) to compare thyroid volume (TV) results with the WHO International reference. METHODS: Five hundred and thirty schoolchildren (6-15 years) were studied from two districts (Baroda and Dang) and data were collected on dietary habits and parameters such as height, weight, thyroid size by palpation and ultrasonography, urinary iodine (UI), and blood thyroid stimulating hormone (TSH). Drinking water was analyzed for iodine content and food articles for goitrogens. RESULTS: In Gujarat children median UI (interquartile range)=56 (30-96)microg/l, mean TSH=1.71 +/- 2.10mU/l, goiter by palpatio n = 30%, and median TV = 27.8 (23-35)ml. Females had lower median UI (48 (27-82) microg/l) and higher mean TSH levels (2.0 +/- 2.5mU/l) than males. Applying the WHO ultrasonography reference to Gujarat children resulted in an enlarged TV-for-body surface area in almost 100% of subjects. Ninety-nine percent of females and 95% of males had enlarged TV-for-age. Three to eight times larger TV were seen in all subjects as compared with European children. Dang children were severely malnourished. Flavonoids like vitexin, glucosyl vitexin and apigenin were detected in pearl millet. Apigenin was never identified in pearl millet. Dang district water was lacking in iodine content. CONCLUSIONS: IDD is a severe public health problem in Gujarat. Baroda district is a new pocket of IDD. High amounts of dietary flavonoids in Baroda and Dang districts, and lack of iodine in Dang water, account for IDD. TV measurement by ultrasound is the best prevalence indicator of IDD.

Impact of protein energy malnutrition on thyroid size in an iodine deficient population of Gujarat (India): Is it an aetiological factor for goiter?

OBJECTIVE: To assess the severity of protein energy malnutrition (PEM) in iodine deficient subjects and to assess the impact of PEM on thyroid size. METHODS: 1002 subjects (530 school-aged children and 472 adults) were assessed for PEM by direct anthropometric measurements of height, weight, triceps skinfold (TSF) thickness, mid upper arm circumference (MUAC) and thigh circumference (TC), and derived indices of body surface area (BSA), body mass index (BMI), and Z-scores for weight-for-age (WAZ), height-for-age (HAZ), and weight-for-height (WHZ). Severity of PEM was based on the World Health Organization (WHO) criteria and the threshold on the Waterlow classification. Thyroid size was measured by ultrasonography to determine the thyroid volume (TV). Linear regression analysis was performed between TV and anthropometric parameters. RESULTS: Children had severe PEM as evident from the WHO percentage prevalence of stunting (HAZ<-2SD)=64% (where <-2SD is the Z-score deficit), wasting (WHZ<-2SD)=43%, underweight (WAZ<-2SD)=82% and BMI<16 kg/m=90%. Waterlow classification showed that children were either stunted or wasted, or stunted and wasted, or stunted and obese. Nearly 100% (529/530) of the children had goiter as evidenced from enlarged TV-for-BSA when compared with the WHO reference. There was a weak but statistically significant (P<0.05) positive correlation between TV and BSA, weight, height, MUAC, TC and HAZ but a negative correlation between TV and WHZ, BMI and TSF (r=-0.1-0.2). Adults had PEM as evident from BMI<18.5 kg/m in 54% subjects. Median MUAC=22.7 cm reveals prolonged severe PEM. Eighty-two percent had enlarged TV (>20 ml). There was a significant (P=0.01) negative correlation between TV and MUAC. CONCLUSIONS: (i) The severity of acute (wasting) and chronic (stunting) PEM is very high in Gujarati children. They are stunted or wasted, or stunted and wasted, or stunted and obese. Gujarati adults are thin with low protein and fat reserves. (ii) Anthropometric parameters showed a significant (P<0.001) correlation (r=0.1-0.2) with thyroid size. (iii) Higher prevalence of goiter may be due to macro-nutrient malnutrition (PEM) in the face of micro-nutrient malnutrition (iodine deficiency disorders, IDD).

Amiodarone induces a different pattern of ultrastructural change in the thyroid to iodine excess alone in both the BB/W rat and the Wistar rat.

Amiodarone (AMD)-induced toxicity can be a life-threatening complication which limits the use of amiodarone as an anti-arrhythmic agent. The aim of the present study was to determine the nature of AMD toxicity by comparing ultrastructural changes induced by AMD and equivalent amounts of iodide in two animal models, the Wistar and the autoimmune BB/W rat. Rats were divided into control (water), AMD- (30 mg AMD/kg) or iodide-treated (10 mg/kg) groups. Thyroids were removed at 15 weeks and processed for electron microscopy. We found that AMD induced specific ultrastructural changes of thyroid cytotoxicity in both rat models, which were distinct compared with changes induced by excess iodide alone. Specific changes included marked distortion of thyroid architecture, evidence of necrosis and apoptosis, inclusion bodies, lipofuscinogenesis and markedly dilated endoplasmic reticulum (ER). Our data indicate that AMD is directly cytotoxic to the thyroid an effect mediated by disruption of subcellular organelle function. ER dilatation is suggestive that AMD cytotoxicity may be mediated through disruption of the protein sorting pathways leading to a drug-induced form of ER storage disease. The predilection of the thyroid to AMD may be explained by the additive effects of excess iodine and AMD drug toxicity on protein sorting pathways.

Iodide induced lymphocytic thyroiditis in the BB/W rat: evidence of direct toxic effects of iodide on thyroid subcellular structure.

A high dietary iodine intake accelerates the development of lymphocytic thyroiditis (LT) in the BB/W rat. Our previous studies have defined the temporal sequence of the immunological events triggered by excess iodide intake in these animals. It was still not clear, however, whether these observed immunological changes were a direct effect on immune effector cells, or whether they represented a secondary response to a toxic effect of iodine on thyroid tissue. In the present study, the effect of excessive iodine intake on the subcellular structure of the BB/W rat thyroid gland, particularly, whether iodide had a toxic effect independent of its immune response has been examined. BB/W rats were exposed, prenatally through maternal drinking water, to excessive iodide at two doses (Moderate 3 x 10(-6) M iodide/l; High 3 x 10(-3) M iodide/l); a third group of BB/W rats was given tap water; till 12 weeks postnatal age. Two groups of Wistar rats received high dose iodide water or tap water for the same period of time and served as controls. Thyroid gland ultrastructure was determined by electron microscopic (EM) examination. Thyroid 125I uptake and perchlorate discharge tests were also performed in separate experiments. We found that thyroid glands of non-iodine supplemented Wistar rats were morphlogically normal under EM. There were no overt changes in the iodide treated Wistar rats. By contrast, iodide treated BB/W rats exhibited marked accumulation of secondary lysosomes and lipid droplets; markedly swollen and disrupted mitochondria and extreme dilatation of rough endoplasmic reticulum (RER).(ABSTRACT TRUNCATED AT 250 WORDS)

Iodine induced lymphocytic thyroiditis in the BB/W rat: early and late immune phenomena.

The effect of iodine excess on thyroid function and on the immunological sequence of events leading to lymphocytic thyroiditis (LT) was studied in the NB subline of BB/W rats to determine the mechanisms by which the level of iodine intake influences the development of LT in this animal model. Iodine supplemented water (500 micrograms/l, Group 1 or 500 mg/l, Group 2) or non-iodine supplemented tap water (Group 3) was given to breeding pairs and their offspring ad libitum. A Wistar rat group, also given tap water (Group 4) served as controls. To determine the immunological sequence of events, the phenotypic nature of the infiltrating thyroid lymphocytes was examined by specific immunoperoxidase staining in BB/W and Wistar rats at 6, 9, 12, and 15 weeks. Antigen-presenting cells and class II (Ia) antigen expression on thyrocytes were also examined. The first immunological event apparent in the iodine-treated BB/W rats was a sharp increase in the number of Ia positive dendritic cells at 9 weeks compared with control BB/W and Wistar rats. In the iodine excess groups dendritic cells were associated with scattered areas of lymphocytic infiltration, comprising predominantly T helper cells (W3/25). T suppressor cells (OX 8) and IL-2 receptor positive activated T-cells (OX 39) were both present in small numbers. B-cells (OX 12) were absent. In addition, thyrocytes did not exhibit Ia antigen expression. By contrast, lymphocytic infiltration was not found at 9 weeks in control BB/W rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Excess iodine induces the expression of thyroid solid cell nests in lymphocytic thyroiditis-prone BB/W rats.

Previous epidemiological studies have suggested that lymphocytic thyroiditis and/or an increased iodine intake may be risk factors for the development of thyroid cancer. We previously reported that excess iodine accelerated the development of thyroid lymphocytic infiltration (LI) in the autoimmune BB/W rat model. We also found that excess iodine increased thyroid cell proliferation in a disordered manner. The present study was designed to further explore these observations and to address the question as to whether excess iodine under certain conditions predisposes the thyroid gland to neoplasia. To test this hypothesis, the lymphocytic thyroiditis-prone BB/W rat was exposed to excess iodine in drinking water. Ten BB/W rats at 4 weeks of age were given iodine water (NaI 0.05%) for 10 weeks, whilst another 10 BB/W rats were given tap water and served as controls. Eighteen normal Wistar rats were also divided into excess iodine and control groups, served as a comparison to the BB/W rats. We found that an excess iodine intake accelerated the development of LI in the BB/W rat. Severe LI was usually accompanied by prominent thyroid cell proliferation, evident as numerous microfollicles and cell masses, not forming normal thyroid follicles. Numerous lymphocytes and plasma cells often encroached on these areas of increased cellular proliferation. The surprising feature, and a possible indicator of activated thyroid cell proliferation, was the high incidence of thyroid solid cell nest-like lesions (SCN) in the iodine treated BB/W rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Expression of beta2-thyroid hormone receptor in euthyroid and hypothyroid rat pituitary gland: an in situ hybridization and immunocytochemical study.

Recently, we have shown an extended distribution pattern of the TR-beta2 isoform in specific sites of rat brain which may be indicative that the localization of this receptor also confers functional specificity. The beta2 thyroid hormone receptor (TR-beta2) is by far the most abundant isoform in the pituitary, although transcripts of TR-alpha and TR-beta1 genes have been reported in developmental and adult rat pituitary gland. Using both in situ hybridization histochemistry (ISH) and immunocytochemistry, we mapped the expression of beta2 thyroid hormone receptor mRNA and protein in euthyroid and hypothyroid adult rat pituitary, particularly in relation to the thyrotrope population. TR-beta2 mRNA localization by ISH showed an anteromedial spatial distribution pattern in euthyroid rat anterior pituitary gland. This localization coincided with the immunostaining pattern for thyrotropes. TR-beta2-immunoreactive cells showed strongly positive signals in the nuclei. Hypothyroidism, induced by propylthiouracil (PTU), abolished the specific localization of TR-beta2 mRNA and upregulated the transcription of TR-beta2 mRNA in vivo and in vitro. Image analysis revealed that the optical density signals within hypothyroid rat pituitary were significantly stronger (2.6-fold) compared with euthyroid counterparts. This correlated strongly with an increased number and staining of TR-beta2 protein positive cells, demonstrating both nuclear and cytoplasmic staining. In response to thyroid hormone deficiency, there was also a marked percentage increase in the thyrotrope population from 10 to 20% of anterior pituitary cells to approximately 80%. In conclusion, these results demonstrate the specific localization of TR-beta2 to the anterior pituitary, especially to the thyrotrope population, and its regulation by thyroid hormone. Hypothyroidism leads to an upregulation of TR-beta2 mRNA and protein in the anterior pituitary, explained not only by an absolute increase in the percentage of thyrotropes but increased expression of TR-beta2 mRNA and protein per cell. These data allude to the TR-beta2 isoform playing a critical role in thyroid hormone-dependent TSH gene expression, although contributions from the other TR isoforms may still remain important.

Endemic cretinism: toward a unifying hypothesis.

Based on our data, the clinical picture of endemic cretinism results from the product of two pathophysiological events. Both events share a common feature, namely iodine deficiency, but act at different points in time. The first event occurs in all cretins and represents the prenatal action of thyroid hormone deficiency on brain development, transmitted vertically from mother to fetus, resulting in the neurological disorder of endemic cretinism. A consistent pattern and intensity of neurological, intellectual, and audiometric deficit is common to and equally present in all types of endemic cretin. The nature of these deficits points to an intrauterine insult to the developing fetal nervous system around the time of the midtrimester. The second event represents the postnatal action of thyroid hormone deficiency on somatic as well as brain development. Whereas previous workers had attributed the differences in the clinical presentation of endemic cretinism to the presence or absence of neurological features (i.e. prenatal hypothyroidism), the distinction between the types of endemic cretin can be related to the length and severity of postnatal thyroid hormone deficiency. Endemic cretins with predominant neurological features have had only transient hypothyroidism in the postnatal period, evidenced by their near normal thyroid function and by a lack of hypothyroid clinical features. By contrast, cretins with marked myxedematous features were characterized by permanent and severe postnatal thyroid hormone deficiency. These cretins, in addition to signs of neurological damage, were typically dwarfed, sexually immature, with marked clinical features of myxedema. This second event, influenced by the thyroid gland's morphologic response to its environment (goiter or thyroid atrophy), dictates the final clinical outcome. In conclusion, our hypothesis states that the clinical expression of endemic cretinism is determined by the sum of two pathophysiologic processes. The first process is fetal hypothyroidism which results in the neurological damage of the disorder and the second process is the duration and magnitude of postnatal hypothyroidism which dictates the final clinical appearance.