Increased TSH Concentrations Research Articles

Subclinical Hypothyroidism in Adults- to Treat or Not?

Background: Subclinical hypothyroidism (ScHt) is a condition in which the Laboratory reports show normal T3 or FT3, normal T4 or FT4, and increased TSH concentrations, associated with few or no signs & symptoms of hypothyroidism. ScHt prevalence is estimated to be ranging from 4% to 20% of adults, with a higher prevalence in women, older people, and those with thyroid autoimmunity. It is higher in iodine-sufficient areas and genetics also plays a role. ScHt can progress to overt hypothyroidism, especially if antithyroid antibodies are present. It has been associated with adverse metabolic parameters like dyslipidaemia, reproductive, maternal-foetal, cardiovascular, neuromuscular, and cognitive abnormalities. ScHt among pregnant women is significant as the prevalence of overt & ScHt among them is reported to be 2.5 % and almost fourfold (9.54%) respectively. The good news is that half of the cases resolve spontaneously in within 2 years. Methods & Materials: This article is an outcome of literature review following the author and his son’s annual blood test results showing indications of ScHt in late February 2024. Results: The results of annual blood tests in a recognised laboratory showed TSH levels of 6.233 and 7.529 respectively for the author and his son respectively. The authors Hb1Ac were 6.4 despite being just on oral anti-diabetics (with diet control and exercise routine) since 1991, indicative of a good management. It was surprising to note that both have ScHt. However, after an intensive literature search and discussions decided for “a wait and watch strategy” instead for jumping for treatment. Conclusion: In India 4% to 20% of adults have subclinical hypothyroidism, with a higher prevalence in women, older people, and those with thyroid autoimmunity. Though ScHt can progress to overt hypothyroidism, especially if antithyroid antibodies are present, half of the cases are expected resolve spontaneously in within 2 years. As most endocrinologists, Cardiologists and Public health professionals in India do not recommend treatment for 1-2 year unless either i) when TSH >10 mIU/L, or signs become explicit, or ii) Cardiovascular risk individuals, we have decided to monitor the progress for entire 2024 with quarterly assessments of the parameters.

Chronic Kidney Disease affects Thyroid Hormones

Kidney disease is one of the causes of death in many countries around the world. This study found that chronic kidney disease affects thyroid hormone formation, release, and storage. The results show a decrease in T3 and T4 thyroid hormones and an increase in TSH hormone in both sexes and people of different ages. The research aims to study the effect of chronic kidney disease on the thyroid gland’s activity and its deficiency’s effect on health ailments. Results showed a significant decrease in T3 concentration in patients at the probability level (p ≤ 0.05) (0.8±0.1) compared with the control group (1.0±0.1). Additionally, a significant decrease in T4 concentration at the probability level (p ≤ 0.05), (6.8±1.5) compared with the control group (8.7±0.9) and a significant increase in TSH concentration at the probability level (p ≤ 0.05), (4.8±0.6) compared with the control group (1.2±0.5). The CDK affects thyroid hormones; low T3 and T4 are the most common thyroid dysfunction. High TSH, enlarged thyroid gland, hypothyroidism, thyroid dysfunction. Keywords: CKD, Thyroid Hormones, Thyroid dysfunction.

Chronic Kidney Disease affects Thyroid Hormones

Kidney disease is one of the causes of death in many countries around the world. This study found that chronic kidney disease affects thyroid hormone formation, release, and storage. The results show a decrease in T3 and T4 thyroid hormones and an increase in TSH hormone in both sexes and people of different ages. The research aims to study the effect of chronic kidney disease on the thyroid gland’s activity and its deficiency’s effect on health ailments. Results showed a significant decrease in T3 concentration in patients at the probability level (p ≤ 0.05) (0.8±0.1) compared with the control group (1.0±0.1). Additionally, a significant decrease in T4 concentration at the probability level (p ≤ 0.05), (6.8±1.5) compared with the control group (8.7±0.9) and a significant increase in TSH concentration at the probability level (p ≤ 0.05), (4.8±0.6) compared with the control group (1.2±0.5). The CDK affects thyroid hormones; low T3 and T4 are the most common thyroid dysfunction. High TSH, enlarged thyroid gland, hypothyroidism, thyroid dysfunction. Keywords: CKD, Thyroid Hormones, Thyroid dysfunction.

Polychlorinated biphenyls and thyroid function: a scoping review.

Numerous evidence indicates the association between polychlorinated biphenyls (PCBs), an endocrine disrupter, with thyroid hormone disruption, contradictory findings also exist. Herein, we tried to address this question by performing a scoping review. The search was performed on PubMed, Scopus, Web of Science, and Google Scholar databases from 2010 onwards. Animal studies on PCBs' effect on thyroid function were searched. The SYRCLE's RoB scale assessed the risk of bias. I2 and Q tests are used for investigating heterogeneity. A random-effects model with the pooled standard means difference (SMD) and 95% confidence interval (CI) was performed for the TSH, TT4, TT3, and FT4 outcomes using Comprehensive Meta-Analyses (CMA) Software version 3. Also, we conducted subgroup analyses based on the different types of PCB. The initial search identified 1,279 publications from the main databases 26 of them fulfilled our eligibility criteria for the study, and then five studies among selected studies had sufficient data for analysis. Meta-analysis of data revealed that Aroclor 1260 (SDM: -0.47, 95% CI: -0.92, -0.01, p=0.044) and PCB 126 (SDM: 0.17, 95% CI: -0.40, 0.75, p=0.559) significantly increased TSH concentration in the exposed groups vs. the control groups. Related to the effects of PCBs on the TT4, our findings indicated a significant reduction the TT4 concentration of animals exposed to Aroclor 1260 (SDM: -5.62, 95% CI: -8.30, -2.94, p=0.0001), PCB 118 (SDM: -6.24, 95% CI: -7.76, -4.72, p=0.0001), PCB 126 (SDM: -1.81, 95% CI: -2.90, -0.71, p=0.001), and PCB 153 (SDM: -1.32, 95% CI: -2.29, -0.35, p=0.007) vs. the controls. Our meta-analysis indicated a significant increase in TT3 concentration following exposure to PCB 118 and PCB 153 (SDM: -0.89, 95% CI: -1.36, -0.42, p=0.0001, and SDM: -1.45, 95% CI: -2.15, -0.75, p=0.0001, respectively). Aroclor 1254 and PCB 126 significantly decreased TT3 concentration (SDM: 1.25, 95% CI: 0.29, 2.21, p=0.01 and SDM: 3.33, 95% CI: 2.49, 4.18, p=0.0001, respectively). PCB 126 significantly decreased FT4 in the exposed groups vs. the control groups (SDM: -7.80, 95% CI: -11.51, -5.35, p=0.0001). Our findings showed an association between PCBs exposure and hypothyroidism in rodents, fish, and chicken embryos. Regarding to the most evidence of hypothyroidism effects of PCBs in animal species, it is necessary to consider large cohort studies to address the association between PCBs exposure and thyroid function impairment in humans.

A novel mutation in TANGO2 gene associated with recurrent muscle weakness with rhabdomyolysis , metabolic encephalopathy and cardiac arrhythmia: a case report

Background TANGO2 depletion was found to cause clinically recognizable multi-organ involvement disorder in pediatrics with episodic muscle weakness recurrent rhabdomyolysis, intellectual disability, metabolic encephalomyopathic crises and cardiac arrhythmia. TANGO2 deficiency is also referred to as \"metabolic encephalomyopathic crises, recurrent, with rhabdomyolysis, cardiac arrhythmias, and neurodegeneration\" (MECRCN) in OMIM. * 616830 Case presentation We report a case of a 4-year-old Saudi boy from a consanguineous Saudi family with two uncles deceased at 3 year of age with recurrent muscle weakness and hyperammonemia of unknown cause .Patient in last attack progressed to severe metabolic encephalomyopathic crisis that required assisted ventilation for 4 months, complicated with life threatening cardiac tachyarrhythmia. Laboratory findings of hypoglycemia, mild hyperammonemia , severely elevated plasma Creatine Kinase, myoglobinuria , lactic acidosis and increased TSH concentration indicating hypothyroidism have been documented. The clinical profile was highly suggestive of TANGO2-realted disorder. Direct DNA sequence analysis of the entire coding regions of TANGO2 gene identified a novel homozygous deletion for three nucleotides in exon 2 (c.11_13delTCT) resulting in amino acid deletion (phenylalanine) at position 5. Conclusion This report illustrates the importance of collating clinical data and keeping a high index of suspicion in order to reach to the diagnosis.

Utility of a canine TSH assay for diagnosis and monitoring of feline hyperthyroidism.

This retrospective study was initiated to evaluate the utility of TSH measurements using a common canine TSH assay to diagnose and monitor feline hyperthyroidism after radioiodine or thyreostatic drug treatment. The electronic database of the University of Veterinary Medicine Vienna was searched for combined TSH and T4 measurements. 217 pairs of TSH and T4 from 136 cats with possible hyperthyroidism were assigned to group A (untreated; n = 24) and B (treated; n = 193). Measurements in group B were then subcategorized according to T4 concentrations (reference range 15-50 nmol/L): group B1 = elevated T4 (n = 46), group B2 = normal T4 (n = 84) and group B3 = decreased T4 (n = 63). Group B2 was further divided into cats with low normal (group B2a; n = 35), medium normal (group B2b; n = 29) and high normal (group B2c; n = 20) T4 concentrations. TSH was detectable in 4 (17 %) of the 24 untreated cats (group A) and did not return to normal despite seemingly successful therapy in two. Increased TSH concentrations were observed in 3.6 % of the treated cats in group B2 and 2.9 %, 6.9 %, and 0 % in subgroups B2a, B2b and B2c, respectively. Forty-four percent of the treated cats with a decreased T4 (group B3) had an increased TSH concentration. TSH correlated with treatment length (r = 0.358, p = 0.004) and was significantly higher in cats treated for more than 3 months (p = 0.008). TSH was detectable in a significant number of untreated hyperthyroid cats and thus this parameter should not be used to definitively rule out feline hyperthyroidism. Furthermore, the very low prevalence of increased TSH concentrations in treated hyperthyroid cats with a normal T4 and cost benefit calculations do not support the routine measurement of TSH in these cats. The fact that TSH correlated with time since treatment start and 56 % of the cats with a decreased T4 had TSH concentrations within the reference limits, suggests delayed recovery of the pituitary thyrotrophs which might explain the low prevalence of subclinical hypothyroidism in the present study. TSH measurement in cats with suspected or treated hyperthyroidism using a canine assay lacks diagnostic sensitivity and can only complement therapeutic decision-making.

The Effect of Recombinant Human TSH on Sclerostin and Other Selected Bone Markers in Patients after Total Thyroidectomy for Differentiated Thyroid Cancer.

The direct effect of TSH on bone metabolism in vivo is difficult to capture as the changes of its concentrations are followed by respective alterations of thyroid hormone levels. We evaluated the effect of recombinant human TSH (rhTSH) on sclerostin and other bone markers in 29 patients after total thyroidectomy for differentiated thyroid cancer (DTC), without any signs of disease recurrence, who received L-thyroxine, most at non-suppressive doses. For two consecutive days, the patients were administered a standard dose of 0.9 mg rhTSH, i.m. Concentrations of sclerostin, osteocalcin, β-CrossLaps, PTH, and some other parameters, were measured before and five days after the first rhTSH administration. The greater the increase in TSH concentration (∆TSH), the greater the decrease in: ∆sclerostin (r = −0.672; p < 0.001), ∆β-CrossLaps (r = −0.580; p < 0.001) and ∆osteocalcin (r = −0.405; p = 0.029) levels, were recorded. The degree of TSH increase depended on the baseline PTH (r = 0.651; p < 0.001), age, and creatinine concentrations. rhTSH strongly inhibited bone turnover, thus, TSH—independently of thyroid hormones—exerted a direct protective effect on bone metabolism. Baseline PTH affected the magnitude of TSH increase and the degree of lowering in sclerostin and β-CrossLaps that suggest factors affecting PTH may play a role in the effect of TSH on the bone.

Short Call Abstracts

Short Call Abstracts

Biochemically diagnosed hypothyroidism and postoperative complications after cardiac surgery: a retrospective cohort analysis.

To determine whether hypothyroidism is associated with cardiovascular complications and surgical wound infections after cardiac surgery. Patients were categorized as: (1) hypothyroid [patients with increased TSH concentrations (≧ 5.5mIU/L) within 6months prior to surgery]; (2) corrected hypothyroid [diagnosis of hypothyroidism any time before surgery or on preoperative thyroid supplementation and normal TSH concentration (0.4 [Formula: see text] TSH [Formula: see text] 5.5 mIU/L]; and (3) euthyroid [no hypothyroid diagnosis and not on preoperative thyroid supplementation and normal TSH concentrations (0.4-5.5 mIU/L)]. We conducted pairwise comparisons among the three groups using inverse probability of treatment weighting. We compared the groups on postoperative myocardial infarction, cardiac arrest, atrial fibrillation, and a composite of surgical wound infections and postoperative vasopressor use using multivariable logistic regression models. We compared the groups on ICU and hospital length of stay using Cox proportional hazards regression. Hypothyroidism was associated with a lower risk of atrial fibrillation than euthyroidism, with an estimated relative risk (99.4% CI) of 0.71 (0.56, 0.89); P < 0.001. However, none of the other pairwise comparisons on myocardial infarction, cardiac arrest, and atrial fibrillation were significant. Corrected hypothyroid patients were slightly more likely to be discharged from hospital at any given time than euthyroid patients (hazard ratios (99.6% CI), 1.18 (1.07, 1.30); P < 0.001), but no other pairwise comparisons for secondary outcomes were significant. Hypothyroidism was associated with lower risk of atrial fibrillation than euthyroidism, and corrected hypothyroidism was associated with a shorter length of stay than euthyroidism.

Higher Incidence Rates of Hypothyroidism and Late TSH Rise in Preterm Very-Low-Birth-Weight Infants at a Tertiary Care Center

Background/Aims: Preterm newborns with a very low birth weight (VLBW) of < 1,500 g have an atypical form of hypothyroidism with a delayed rise in TSH, necessitating a second newborn screening specimen collection. The aims of this study were to survey the compliance with second newborn screening to detect delayed TSH rise in VLBW preterm infants at a tertiary care center, and to determine the rate of atypical hypothyroidism. Methods: Retrospective review of the records of 104 preterm VLBW infants. Late TSH rise was defined as an increase in TSH concentration after 14 days of age in the presence of a normal initial screen. Results: The compliance rate was 92% for the second screening. High rates of hypothyroidism (16.3%) and of late TSH rise (4.8%) were detected. Patients with hypothyroidism had a significantly lower birth weight (p = 0.01) and longer hospital stay (p = 0.004). Patients with late versus those with early TSH rise had a significantly lower mean birth weight (851 ± 302 vs. 1,191 ± 121 g, p = 0.004). Conclusion: The rates of early and late TSH rise in this VLBW population were higher than those in the literature and could be due to the use of povidone-iodine disinfectants. The yield of a second TSH screening in this study was high indicating the need for vigilance in screening VLBW preterm infants.

Effects of the environmental endocrine disrupting compound benzo[a]pyrene on thyroidal status of abu mullet (Liza abu) during short-term exposure

Benzo[a]Pyrene (BaP) is a ubiquitous polycyclic aromatic hydrocarbon (PAH) that has been shown to disrupt the metabolism of thyroid hormone. Then, the present investigation aimed to study the effects of BaP on thyroid function in Liza abu. Fish were injected with 2, 10 and 25 mg/kg-bw of BaP. Samples were taken from blood, thyroid and muscle tissues at days 1, 2, 4, 7, and 14. Blood was evaluated for changes in the plasma levels of TSH, T3 and T4. Also, BaP bioaccumulation in the fish muscle was measured. Thyroid tissues were processed for routine histology. BaP concentration in the muscle of treated fish reached a maximum level after 4 days. Exposure of fish to BaP resulted in a significant decrease in T3 and T4 plasma level and increase in TSH concentration up to day 4. Also some pathological alterations were observed in BaP-exposed fish such as hemorrhage and increased number of large follicles with squamous epithelium. In conclusion, according to the results of the present investigation, short term exposure to sublethal concentrations of BaP significantly affected thyroid function in fish. The results revealed BaP ability to alter thyroid function.

Current loss-of-function mutations in the thyrotropin receptor gene: when to investigate, clinical effects, and treatment

Thyroid-stimulating hormone receptor (TSHR) loss-of-function (LOF) mutations lead to a wide spectrum of phenotypes, ranging from severe congenital hypothyroidism (CH) to mild euthyroid hyperthyrotropinemia. The degree of TSH resistance depends on the severity of the impairment of the receptor function caused by the mutation and on the number of mutated alleles In this review data about genotype-phenotype correlation and criteria for clinical work-up will be presented and discussed. Complete TSH resistance due to biallelic LOF TSHR mutations must be suspected in all patients with severe not syndromic CH and severe thyroid hypoplasia diagnosed at birth by neonatal screening. Partial forms of TSH resistance show a more heterogeneous hormonal and clinical pattern . In these cases TSH serum levels are above the upper limit of normal range for the age but with a very variable pattern, free thyroxine (T4) concentrations are within the normal range and thyroid size can be normal or hypoplastic at ultrasound scan. An early substitutive treatment with L-T4 must be mandatory in all patients with severe CH due to complete uncompensated TSH resistance diagnosed at birth by neonatal screening. The usefulness of substitutive treatment appears much more controversial in patients with subclinical hypothyroidism due to partial TSH resistance in whom the increased TSH concentration should be able to compensate the mild functional impairment of the mutant receptor. Together with standard criteria we recommend also an accurate clinical work-up to select patients who are candidates for a LOF TSHR mutation. Conflict of interest:None declared.

Blunted nocturnal TSH surge does not indicate central hypothyroidism in patients after pituitary surgery.

The thyrotropin-releasing hormone stimulation test (TRH test) is commonly used as part of the endocrine evaluation after pituitary surgery. However, some patients with a normal thyrotropin (TSH) response to TRH after pituitary surgery develop central hypothyroidism during follow-up. On the other hand, hypothyroidism does not necessarily ensue in patients with a blunted TSH response. As TSH is secreted in a pulsatile fashion with maximum secretion in the early morning, we investigated whether measurement of the nocturnal TSH surge is useful for predicting development of thyrotropic function after pituitary surgery. Serum TSH concentrations were measured at hourly intervals from 16.00 h to 06.00 h in 13 healthy volunteers and in 10 patients within 2 weeks after pituitary surgery. A standard TRH test using i.v. injection of 200 microg synthetic TRH was performed the next morning. Three and six months later thyroid function was reassessed in all patients by measuring thyroid hormones and TSH. Healthy volunteers showed a clear nocturnal TSH surge from a nadir of 0.55 +/- 0.27 microIU/ml at 18.00 h to a peak concentration of 1.82 +/- 0.97 microU/ml at 06.00 h (p = 0.0015). DeltaTSH during TRH test was 6.31 +/- 2.27 microIU/ml. In contrast, following pituitary surgery, patients invariably showed a blunted nocturnal increase in TSH concentration, which was 0.27 +/- 0.20 microIU/ml at 18.00 h and 0.33 +/- 0.26 microIU/ml at 06.00 h (p = 0.044). DeltaTSH during TRH test was 1.99 +/- 2.51 microIU/ml and was subnormal in 8 out of 10 patients. Levothyroxine supplementation was initiated in two of these patients, because free T4 levels were also subnormal and clinical hypothyroidism was present. In the remaining patients with subnormal TRH response, no case of central hypothyroidism was identified at the follow-up visits after 3 and 6 months. We conclude from these data that both nocturnal TSH surge and TRH test are subnormal after pituitary surgery and do not indicate that central hypothyroidism will develop.

Relations of Thyroid Function to Body Weight&lt;subtitle&gt;Cross-sectional and Longitudinal Observations in a Community-Based Sample&lt;/subtitle&gt;

Overt hypothyroidism and hyperthyroidism may be associated with weight gain and loss. We assessed whether variations in thyroid function within the reference (physiologic) range are associated with body weight. Framingham Offspring Study participants (n=2407) who attended 2 consecutive routine examinations, were not receiving thyroid hormone therapy, and had baseline serum thyrotropin (TSH) concentrations of 0.5 to 5.0 mIU/L and follow-up concentrations of 0.5 to 10.0 mIU/L were included in this study. Baseline TSH concentrations were related to body weight and body weight change during 3.5 years of follow-up. At baseline, adjusted mean weight increased progressively from 64.5 to 70.2 kg in the lowest to highest TSH concentration quartiles in women (P< .001 for trend), and from 82.8 (lowest quartile) to 85.6 kg (highest quartile) in men (P= .007 for trend). During 3.5 years of follow-up, mean (SD) body weight increased by 1.5 (5.6) kg in women and 1.0 (5.0) kg in men. Baseline TSH concentrations were not associated with weight change during follow-up. However, an increase in TSH concentration at follow-up was positively associated with weight gain in women (0.5-2.3 kg across increasing quartiles of TSH concentration change; P< .001 for trend) and men (0.4-1.3 kg across quartiles of TSH concentration change; P= .007 for trend). Thyroid function (as assessed by serum TSH concentration) within the reference range is associated with body weight in both sexes. Our findings raise the possibility that modest increases in serum TSH concentrations within the reference range may be associated with weight gain.

Hypothyroid‐Associated Central Vestibular Disease in 10 Dogs: 1999–2005

Background:With the exception of myxedema coma, central nervous system signs are rare in hypothyroid dogs.Hypothesis:Central vestibular dysfunction is a possible and reversible manifestation of hypothyroidism.Animals:Medical records of dogs with vestibular dysfunction and hypothyroidism were reviewed. Of 113 records identified, 10 dogs with at least 2 concurrent clinical neurologic abnormalities localizable to the central vestibular system were included.Methods:Retrospective, descriptive study.Results:Median age at diagnosis was 7 years (range, 5–10 years). All dogs were referred for progressive neurologic disease. Lesions were localized to the myelencephalic region in 5 dogs and to the vestibulocerebellum in 5 dogs. Two dogs had evidence of multifocal intracranial disease. Non‐neurologic physical abnormalities suggestive of hypothyroidism were absent in 7 of 10 dogs. Hypercholesterolemia was the only consistent clinicopathologic abnormality detected, and was present in 7 of 10 dogs. All dogs had total thyroxine (TT4) and free thyroxine (fT4) concentrations below reference ranges, and 9 of 10 had increased TSH concentrations. Intracranial imaging studies were normal in 5 of 8 dogs, and identified lesions consistent with infarctions in 3 of 8 dogs. Albuminocytologic dissociation was detected in 5 of 6 CSF analyses. Brainstem auditory‐evoked responses disclosed prolonged wave V latencies in 3 of 4 dogs tested. No other causes of central vestibular dysfunction were identified during other diagnostic investigations. The median time from initiation of treatment to clinical improvement was 4 days. Vestibular signs resolved in 9 of 10 dogs within 4 weeks.Conclusions and Clinical Importance: Although the pathogenesis in dogs without evidence of infarction is unknown, central vestibular dysfunction appears to be a rare but reversible neurologic sequelae of hypothyroidism.

Hypothyroid-Associated Central Vestibular Disease in 10 Dogs: 1999–2005

With the exception of myxedema coma, central nervous system signs are rare in hypothyroid dogs. Central vestibular dysfunction is a possible and reversible manifestation of hypothyroidism. Medical records of dogs with vestibular dysfunction and hypothyroidism were reviewed. Of 113 records identified, 10 dogs with at least 2 concurrent clinical neurologic abnormalities localizable to the central vestibular system were included. Retrospective, descriptive study. Median age at diagnosis was 7 years (range, 5-10 years). All dogs were referred for progressive neurologic disease. Lesions were localized to the myelencephalic region in 5 dogs and to the vestibulocerebellum in 5 dogs. Two dogs had evidence of multifocal intracranial disease. Non-neurologic physical abnormalities suggestive of hypothyroidism were absent in 7 of 10 dogs. Hypercholesterolemia was the only consistent clinicopathologic abnormality detected, and was present in 7 of 10 dogs. All dogs had total thyroxine (TT4) and free thyroxine (fT4) concentrations below reference ranges, and 9 of 10 had increased TSH concentrations. Intracranial imaging studies were normal in 5 of 8 dogs, and identified lesions consistent with infarctions in 3 of 8 dogs. Albuminocytologic dissociation was detected in 5 of 6 CSF analyses. Brainstem auditory-evoked responses disclosed prolonged wave V latencies in 3 of 4 dogs tested. No other causes of central vestibular dysfunction were identified during other diagnostic investigations. The median time from initiation of treatment to clinical improvement was 4 days. Vestibular signs resolved in 9 of 10 dogs within 4 weeks. Although the pathogenesis in dogs without evidence of infarction is unknown, central vestibular dysfunction appears to be a rare but reversible neurologic sequelae of hypothyroidism.

Effect of the 2004 Mid Niigata Prefecture Earthquake on Patients with Endocrine Disorders

A major earthquake (Richter scale magnitude 6.8) struck the Chuetsu district of Niigata Prefecture, Japan, a rural area with mountain villages, on October 23, 2004. Strong aftershocks (Grade 5-6 on the Japanese intensity scale, JIS) continued for 2 months. We analyzed the earthquake's impact on 229 patients with various endocrine disorders [6 central diabetes insipidus (CDI), 16 adrenal insufficiency (AI) including 5 panhypopituitarism, 10 ACTH isolated deficiency and 1 Addison's disease, 145 Graves' disease and 62 Hashimoto's disease]. The status of patients with CDI or AI was not adversely affected by the earthquake. Twenty-eight (19%) patients with Graves' disease developed more severe hyperthyroidism; the incidence of developing more severe hyperthyroidism increased with greater degrees of hyperthyroidism. Three (5%) patients with Hashimoto's disease developed increased TSH concentrations. Most patients stayed in their own houses following the first shock. The median PTSD total score for all patients was low. However, the PTSD total score in patients with CDI or Hashimoto's disease was significantly higher than in other patients, while the subscore of mental status in patients with AI was significantly much lower than in other patients. In patients with Hashimoto's disease, patients whose hypothyroidism worsened had higher total and environmental effects score than patients whose hypothyroidism remained stable. Comparing patients whose hyperthyroidism became more severe to those in whom it remained stable, as well as on multiple logistic regression analysis, serum TRAb was found to be a risk factor for developing more severe hyperthyroidism. In conclusion, our findings indicate that Graves' disease patients need to maintain their euthyroid state with a low serum TRAb titer to prevent the development of further thyroid dysfunction after an earthquake, and that all patients should continue to take their medication, since it is likely that their lives will be interrupted by environmental effects owing to earthquake-shock, especially patients with CDI or Hashimoto's disease. Due to the risk of medical facility closure during a disaster, all patients should always have a note or copy of their medical records, including medical history and medications used, to avoid relying on patients remembering their drug names and doses. Furthermore, appropriate information should be provided by all means possible, including the mass media, to affected individuals, particularly those with AI, to decrease the occurrence of adverse consequences.

Dominant inhibition of thyroid hormone action selectively in the pituitary of thyroid hormone receptor-beta null mice abolishes the regulation of thyrotropin by thyroid hormone.

Thyroid hormones, T4 and T3, regulate their own production by feedback inhibition of TSH and TRH synthesis in the pituitary and hypothalamus when T3 binds to thyroid hormone receptors (TRs) that interact with the promoters of the genes for the TSH subunit and TRH. All TR isoforms are believed to be involved in the regulation of this endocrine axis, as evidenced by the massive dysregulation of TSH production in mice lacking all TR isoforms. However, the relative contributions of TR isoforms in the pituitary vs. the hypothalamus remain to be completely elucidated. Thus, to determine the relative contribution of pituitary expression of TR-alpha in the regulation of the hypothalamic-pituitary-thyroid axis, we selectively impaired TR-alpha function in TR-beta null mice (TR-beta-/-) by pituitary restricted expression of a dominant negative TR-beta transgene harboring a delta337T mutation. These animals exhibited 10-fold and 32-fold increase in T4 and TSH concentrations, respectively. Moreover, the negative regulation of TSH by exogenous T3 was completely absent and a paradoxical increase in TSH concentrations and TSH-beta mRNA was observed. In contrast, prepro-TRH expression levels in T3-treated TR-beta-/- were similar to levels observed in the delta337/TR-beta-/- mice, and ligand-independent activation of TSH in hypothyroid mice was equivalently impaired. Thus, isolated TR-beta deficiency in TRH paraventricular hypothalamic nucleus neurons and impaired function of all TRs in the pituitary recapitulate the baseline hormonal disturbances that characterize mice with complete absence of all TRs.

Circulating thyrotropin bioactivity in sporadic central hypothyroidism.

The etiopathogenesis of sporadic central hypothyroidism (CH) involves pituitary and hypothalamic lesions. Pituitary CH (pCH) implies a diminished number of functioning thyrotropes, accounting for the quantitative impairment of TSH secretion. Hypothalamic CH (hCH) is characterized by normal or even increased TSH concentrations and qualitative abnormalities of TSH secretion, including a decreased bioactivity of circulating TSH. However, controversy still exists about the actual occurrence of bioinactive TSH among CH patients, and no data are available in pCH. Therefore, we studied 41 CH patients with different hypothalamic-pituitary disorders. Immunoreactive TSH (TSH-I) ranged from 0.08-11.1 mU/L (normal, 0.24-4.0), free T4 (FT4) ranged from 0.6-8.8 pmol/L (normal, 9-18), and FT3 ranged from 1.2-5.4 pmol/L (normal, 4-8). A blunted TSH response to TRH (<4 mU/L), indicating prevalent pCH, was found in 56% of the patients, and a net TSH-I increment > or =4 mU/L, indicating prevalent hCH, was found in the remaining 44%. Net TSH-I increments showed significant correlation with basal FT4 (P < 0.02), indicating the relevance of pituitary TSH reserve in the pathogenesis of CH. Circulating TSH was immunoconcentrated and tested in bioassay and in ricin affinity chromatography. The ratio between biological (B) and immunological (I) activities of circulating TSH was reduced (n = 25; TSH B/I, 0.38+/-0.19) compared to the values recorded in normal subjects (n = 26; TSH B/I, 1.53+/-0.54; P < 0.001) and primary hypothyroid patients (n = 24; TSH B/I, 0.74+/-0.31; P < 0.001), but no difference between pCH (n = 9; 0.36+/-0.16) and hCH (n = 16; 0.39+/-0.20) was seen. TSH B/I values in CH patients showed a limited overlap with normal values (20%) and a highly significant correlation with the FT3 response to endogenous TRH-stimulated TSH (P < 0.005). The elevated sialylation degree of TSH molecules may explain part of these findings. In conclusion, the secretion of TSH molecules with reduced bioactivity is a common alteration in the patients with hypothalamic-pituitary lesions, contributing along with the impairment of pituitary TSH reserve to the pathogenesis of CH.

Regulation and transfer of a murine model of thyrotropin receptor antibody mediated Graves' disease.

In order to replicate a recently described murine model of Graves' disease, we immunized AKR/N (H-2k) mice i.p., every 2 weeks, with either a clone of fibroblasts expressing both the human TSH receptor (hTSHR) and murine major histocompatibility complex (MHC) class II molecules or with fibroblasts expressing the MHC class II molecules alone. Mice were bled, and their thyroid hormone levels measured, at 6, 12, and up to 18 weeks after the first immunization. Between 11-12 weeks after immunization, a significant number of mice began to die spontaneously and were found to have developed large goiters. Thirty to 40% of mice immunized with hTSHR transfected fibroblasts showed markedly increased serum T3 and T4 hormone levels by 12 weeks compared with controls, with the highest thyroid hormone levels being T3: 420 ng/dl (normal < 70) and T4: 16.5 microg/dl (normal < 5). The murine serum demonstrated the presence of antibodies to the TSHR, as evidenced by inhibition of labeled TSH binding to the hTSHR, and these sera had in vitro thyroid stimulating activity. Many of the hyperthyroid mouse exhibited weight loss and hyperactivity and, on examination, their thyroids had the histological features of thyroid hyperactivity including thyroid enlargement, thyroid cell hypertrophy, and colloid droplet formation--all consistent with Graves' disease. In contrast, a small number of mice (< 5%) developed hypothyroidism with low serum T4 levels and markedly increased TSH concentrations and evidence of thyroid hypoplasia. Both hyperthyroidism and hypothyroidism were successfully transferred to naive mice using ip cells of immunized mice. Surprisingly, hypothyroidism occurred in many recipient mice even after transfer from hyperthyroid donors. These results confirmed that immunization with naturally expressed hTSHR in mammalian cells was able to induce functional TSHR autoantibodies that either stimulated or blocked the mouse thyroid gland and induced hyperthyroidism or thyroid failure. Furthermore, both blocking and stimulating antibodies coexisted in the same mice as evidenced so clearly by the transfer of hypothyroidism from hyperthyroid mice. The addition of a Th2 adjuvant (pertussis toxin) caused approximately 50% of the animals to become hyperthyroid beginning early at 9 weeks, whereas a Th1 adjuvant (CFA) delayed the disease onset such that only 10% were hyperthyroid by 12 weeks. As with human autoimmune thyroid disease, the T cell control of this murine model may be critical and requires more extensive investigation.