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Thursday, May 22, 2008


Fluoride Damages the Thyroid, report shows

Fluoride Damages the Thyroid, report shows
First-ever government review of fluoride/thyroid toxicology shows risk .

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2008-05-19 15:54:10 - There is clear evidence that small amounts of fluoride, at or near levels added to U.S. water supplies,
present potential risks to the thyroid gland, according to the National Research Council's (NRC) first-ever published review of the fluoride/thyroid literature.(A)


Fluoride, in the form of silicofluorides, injected into 2/3 of U.S. public water supplies, ostensibly to reduce tooth decay, was never safety-tested.(B)

"Many Americans are exposed to fluoride in the ranges associated with thyroid effects, especially for people with iodine deficiency," says Kathleen Thiessen, PhD, co-author of the government-sponsored NRC report. "The recent decline in iodine intake in the U.S could
contribute to increased toxicity of fluoride for some individuals," says Thiessen.

"A low level of thyroid hormone can increase the risk of cardiac disease, high cholesterol, depression and, in pregnant woman, decreased intelligence of offspring," said Thiessen.(C)

Common thyroid symptoms include fatigue, weight gain, constipation, fuzzy thinking, low blood pressure, fluid retention, depression, body pain, slow reflexes, and more. It's estimated that 59 million
Americans have thyroid conditions.(D)

Robert Carton, PhD, an environmental scientist who worked for over 30 years for the U.S. government including managing risk assessments on high priority toxic chemicals, says "fluoride has detrimental effects on the thyroid gland of healthy males at 3.5 mg a day. With iodine deficiency, the effect level drops to 0.7 milligrams/day for an average male."(E) (1.0 mg/L fluoride is in most water supplies)

Among many others, the NRC Report cites human studies which show

- fluoride concentrations in thyroids exceeding that found in other soft tissues except kidney

- an association between endemic goiter and fluoride exposure or enamel fluorosis in human populations

- fluoride adversely affects thyroid and parathyroid hormones, which affect bone health

"If you have a thyroid problem, avoiding fluoride may be a good preventive health measure for you," writes Drs' Richard and Karilee Shames in "Thyroid Power."(F).

Over, 1,700 Physicians, Dentists, Scientists, Academics and Environmentalists urge Congress to stop water fluoridation until Congressional hearings are conducted. They cite new scientific evidence that fluoridation is ineffective and has serious health risks. (http://www.fluorideaction.org/statement.august.2007.html)

Please sign the petition and Congressional letter to support these
professionals http://www.FluorideAction.Net

References:

(A) "Fluoride in Drinking Water: A Scientific Review of EPA's
Standards," Committee on Fluoride in Drinking Water, Board on
Environmental Studies and Toxicology, Division on Earth and Life
Studies, National Research Council of the National Academies of
Science. March 2006 Chapter 8
http://www.nap.edu/catalog.php?record_id=11571

"Thyroid Function: Fluoride exposure in humans is associated with
elevated TSH concentrations, increased goiter prevalence, and altered
T4 and T3 concentrations." (Page 262)

"(The thyroid effects are associated with average fluoride intakes
that) will be reached by persons with average exposures at fluoride
concentrations of 1-4 mg/L in drinking water, especially the
children." (Page 260)

(B) Sodium Hexafluorosilicate and Fluorosilicic Acid
Review of Toxicological Literature, October 2001
http://ntp.niehs.nih.gov/ntp/htdocs/Chem_Background/ExSumPDF/Fluorosilicates.pdf

(C) Chemical & Engineering News, "Fluoride Risks Are Still A
Challenge," by Bette Hileman, September 4, 2006,
http://pubs.acs.org/cen/government/84/8436gov1.html

(D) Mary Shomon, About.com Thyroid editor, Patient Advocate --
Author of "The Thyroid Diet" and "Living Well With Hypothyroidism"
http://thyroid.about.com/

(E) Fluoride, "Review of the 2006 National Research Council Report:
Fluoride in Drinking Water," July-September 2006, by Robert J. Carton
http://www.fluorideresearch.org/393/files/FJ2006_v39_n3_p163-172.pdf

(F) Thyroid Power and Feeling Fat Fuzzy or Frazzeled"by Richard
Shames MD & Karilee Shames RN, PhD http://www.thyroidpower.com
http://www.feelingfff.com/


Fluoride/Thyroid Health Effects
http://www.fluoridealert.org/health/thyroid/

Sources of Fluoride
http://www.fluoridealert.org/f-sources.htm

Sulfuryl Fluoride Pesticide Residues Allowed on Foods
http://www.fluoridealert.org/pesticides/sulfuryl.f.all.food.html
United States Department of Agriculture (USDA) National Fluoride
Database of Selected Beverages and Foods
http://www.nal.usda.gov/fnic/foodcomp/Data/Fluoride/Fluoride.html

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Wednesday, May 07, 2008


Read My blog While at work...

While I'm no fan of cheating or lying, or nicking stuff, I had include this because I think it is very clever, heard of it many times but was surprised to find my bloggie here: Catlicious via Workfriendly


enjoy and don't get caught!!

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Monday, May 05, 2008


You've read it right here, T3 and T4 auto antibodies cause spuriously high free T3 serum levels and continuing hypothyoid symptoms when patients are treated to lab reference ranges instead of to cessation of symptoms, Now read on regarding the genetic resistance to thyroid hormone that does exactly the same thing.
Yes, this is why some people need to take much more than the reccommended dosage of thyroid hormone.



http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=296951
Furthermore, the dominant negative inhibition elicited by the P448H receptor mutant at higher T3 concentrations was reversed in the presence of high doses of T3

Dr Lowe in France

(1) is euthyroid before beginning the use of T3, according to thyroid function test results, including a TRH stimulation test;
(2) markedly improves or completely recovers from hypothyroid-like FMS symptoms and signs with supraphysiologic dosages of T3;
(3) after beginning T3 therapy has an extremely high free T3 blood level;
(4) has no evidence of tissue thyrotoxicosis due to the high free T3 level, according to the results of serial ECGs, serum and urine biochemical tests, and bone densitometry.

Most of our euthyroid patients who improve or recover with metabolic rehabilitation involving T3 therapy meet these four criteria. Clearly, this set of findings in many treated euthyroid FMS patients shows that they meet Refetoff's definition of thyroid hormone resistance: "reduced responsiveness of target tissues to concentrations of thyroid hormone that under normal conditions would be excessive" (23).

http://www.sciencedirect.com/science?_ob=ArticleURL&_udi=B6T3G-3YDGFYR-D&_user=10&_coverDate=01%2F25%2F2000&_rdoc=1&_fmt=high&_orig=browse&_cdi=4946&_sort=d&_docanchor=&view=c&_ct=1&_refLink=Y&_acct=C000050221&_version=1&_urlVersion=0&_userid=10&md5=0d9bd777c0288fd48c19d5e77c212a5f

Abstract
Thyroid hormone receptors (T3Rs) both repress and activate gene transcription by interacting with auxiliary factors denoted corepressors and coactivators. Resistance to thyroid hormone (RTH) syndrome in humans is manifested as a failure to respond properly to elevated circulating thyroid hormone. RTH syndrome has been mapped to T3Râ mutations that alter the transcriptional properties of the receptor, resulting in a dominant negative phenotype. We report here a characterization of a series of RTH mutant T3Rs that exhibit unusual interactions with corepressor. Two mutations in receptor helix 11 (Ä430, Ä432) greatly enhance the ability of the mutant receptors to bind to corepressor. A distinct mutation, V264D, in an 'omega loop' region of the receptor, impairs corepressor release but does not fully eliminate the ability to recruit coactivator. These mutations reveal novel determinants that regulate the interaction of the T3R with important ancillary cofactors, and that are disrupted in a human endocrine disease.

http://books.google.com.au/books?id=B9z1W9JNA64C&pg=PA119&lpg=PA119&dq=thyroid+cellular+resistance&source=web&ots=bqImsvUHpn&sig=cWw4WXZBds8OSIgHBRYgEU92kTs&hl=en#PPA121,M1

Dr Gina Honeyman.com
"What lab tests do you want to see to know if I'm on the right thyroid'hormone dosage? My doctor says that lab tests, particularly my TSH, are'the only way to know if I need to change my thyroid medication." –Bob.


While the standard thyroid lab tests including TSH, free T4, free T3, and thyroid antibody group are necessary for your initial evaluation, I do not recheck them to see if you're on the correct dosage. However, if either the thyroid peroxidase antibodies or thyroglobulin antibodies have been elevated I certainly will recheck them to be sure they are being suppressed by your thyroid hormone therapy. The usual system of diagnosis and adjusting thyroid medication dosages
keeps so many people undiagnosed and under-treated that I consider it a threat to public health. I've participated in research projects that have proven that the TSH, free T3 and free T4 do not correlate with patients' metabolic rates. These articles that I coauthored about these studies can be found online at no cost so please feel free to copy them and share them with your prescribing physicians. You can find the studies at these links:
Medical Science Monitor
Thyroid Science online journal
Your prescribing doctor may insist on checking the lab tests since that is the standard of care to which they are held. I'm always glad to discuss this research and my metabolic rehab protocol with your other physicians. The best way to know if you're on the optimal dosage of thyroid hormone is to monitor your responses according to the metabolic rehab protocol and recheck your resting metabolic rate at intervals. Be sure to use my "Are you overstimulated?" form to watch for signs or symptoms of excessive dosing with your thyroid hormone. Please share these forms with your prescribing doctor to let him or her know that
you are carefully watching for this possibility. Some doctors have asked for permission to use my copyrighted form with all of their patients on thyroid medications and I'm always pleased to share this with others.

"I started metabolic rehab because of the same symptoms as a friend of mine, but she's on a much higher dose of Cytomel than I am, and she's not getting well as fast as I am. Do you think she's doing something wrong?" –Maureen R.


There is no way to predict how one person will respond to metabolic rehab compared to another. We all have individual responses and there's no magic in a particular dosage of Cytomel or other thyroid hormone medications. Your friend most likely has a greater degree of cellular resistance to thyroid hormone, meaning that she may have a greater number of thyroid hormone receptors that are not working properly. I can speculate about the reasons this can happen, but the greater value is in your friend continuing to persist with her treatment. She needs to be sure she is using all parts of the protocol. Sometimes people
decline to take nutritional supplements, for example, and this compromises their treatment outcome. She may have other health issues to address at the same time she is dealing with her hypometabolism.

http://www.medscimonit.com/fulltxt.php?ICID=452199


http://www.thyroidscience.com/Criticism/lowe.dec.2006/lowe.critique.T4.T4&T3.Studies.pdf

I looked up the endocrinologist that Dr Lowe referred to and thought this line was important re; treating t3 resistance (TH = thyroid
hormone)

The optimal dose of TH is variable among individuals, and doses of L-T4 as high as 1,000 µg per day may be necessary to achieve the desired effects.
http://jcem.endojournals.org/cgi/content/full/84/2/401


http://www.ncbi.nlm.nih.gov/pubmed/17574009?ordinalpos=4&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Syndromes of reduced sensitivity to thyroid hormone: genetic defects in hormone receptors, cell transporters and deiodination.Refetoff S, Dumitrescu AM.
Department of Medicine, University of Chicago, Chicago, IL 60637, USA. refetoff@uchicago.edu

At least six major steps are required for secreted thyroid hormone (TH) to exert its action on target tissues. Mutations interfering with three of these steps have been so far identified. The first recognized defect, which causes resistance to TH, involves the TH receptor beta gene and has been given the acronym RTH. Occurring in approximately 1 per 40,000 newborns, more than 1000 affected subjects, from 339 families, have been identified. The gene defect remains unknown in 15% of subjects with RTH. Two novel syndromes causing reduced sensitivity to TH were recently identified. One, producing severe psychomotor defects in > 100 males from 26 families, is caused by mutations in the cell-membrane transporter of TH, MCT8; the second, affecting the intracellular metabolism of TH in four individuals from two families, is caused by mutations in the SECISBP2 gene, which is required for the synthesis of selenoproteins, including TH deiodinases.


http://www.ncbi.nlm.nih.gov/pubmed/1580595?ordinalpos=5&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Thyroid hormone resistance.Weiss RE, Refetoff S.
Department of Medicine, University of Chicago, Illinois 60637.

Generalized resistance to thyroid hormone (GRTH) encompasses a heterogeneous group of conditions characterized by reduced responses of target tissues to thyroid hormone due to defects at the site of hormone action. In the majority of patients, GRTH is inherited as a dominant trait associated with mutations in the hormone-binding domain of the thyroid hormone receptor. GRTH serves as a prototype of other resistance syndromes for hormones that act via nuclear receptors.



http://www.ncbi.nlm.nih.gov/pubmed/10487671?ordinalpos=6&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

The thyroid hormone receptor-beta gene mutation R383H is associated with isolated central resistance to thyroid hormone.Safer JD, O'Connor MG, Colan SD, Srinivasan S, Tollin SR, Wondisford FE.
Thyroid Unit, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215, USA. Jsafer@bu.edu

Resistance to thyroid hormone (RTH) action is due to mutations in the beta-isoform of the thyroid hormone receptor (TR-beta). RTH patients display inappropriate central secretion of TRH from the hypothalamus and of TSH from the anterior pituitary despite elevated levels of thyroid hormone (T4 and T3). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-beta. Most individuals with TR-beta mutations have generalized resistance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation. Whether TR-beta mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with striking peripheral sensitivity to graded T3 administration. The subject was enrolled in a protocol in which she received three escalating T3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T3 dose. Although the patient's resting pulse rose only 11% in response to T3, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant to T3 that her serum TSH was not suppressed with 200 microg T3, orally, daily for 4 days. The patient's C-terminal TR exons were sequenced revealing the mutation R383H in a region not otherwise known to harbor TR-beta mutations. Our clinical evaluation presented here represents the most thorough documentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-beta mutation.



http://www.ncbi.nlm.nih.gov/pubmed/15815068?ordinalpos=7&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Resistance to thyroid hormone in a Chinese family with R429Q mutation in the thyroid hormone receptor beta gene.Kong AP, Lam CW, Chan AO, Yiu SF, Tiu SC.
Department of Medicine, Queen Elizabeth Hospital, 30 Gascoigne Road, Hong Kong.

The combination of elevated serum levels of free thyroid hormones with non-suppressed thyroid-stimulating hormone suggests the differential diagnoses of resistance to thyroid hormone or thyroid-stimulating hormone-secreting pituitary tumour. Clinical differentiation of these two conditions can be difficult, because patients with thyroid hormone resistance may exhibit various combinations of hypermetabolic and hypometabolic features, and laboratory results have limited sensitivity and specificity. We report a case of resistance to thyroid hormone in a Chinese family that illustrates this difficulty. The diagnosis could only be confirmed by the identification of a known disease-causing mutation in the thyroid hormone receptor beta gene in peripheral leukocytes. Availability of genetic tests will identify more cases in the future and improve our understanding of this condition.



http://www.ncbi.nlm.nih.gov/pubmed/12946875?ordinalpos=8&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Molecular basis of resistance to thyroid hormone.Yen PM.
Molecular Regulation and Neuroendocrinology Section, Clinical Endocrinology Branch, NIDDK/NIH, Bethesda, MD 20892, USA. pauly@intra.niddk.nih.gov

Resistance to thyroid hormone (RTH) is a syndrome in which patients have raised serum thyroid hormone (TH) levels and raised or inappropriately normal thyrotropin (TSH) levels. In general, patients exhibit TH resistance in the pituitary and peripheral tissues. Novel techniques and genetically engineered mouse model systems have increased our understanding of thyroid hormone receptor (TR) action, and shed new light on the underlying molecular mechanisms for RTH. In particular, we are learning how mutant TRs from RTH patients can block wild-type TR function, with consequent effects in various tissues and cells. This dominant-negative activity has important implications for other hormone-resistant conditions and in hormone-sensitive tumors. This article examines the molecular basis of RTH.



http://www.ncbi.nlm.nih.gov/pubmed/9350446?ordinalpos=9&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Resistance to thyroid hormone.Chatterjee VK.
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, UK. kkc1@mole.bio.cam.ac.uk

Resistance to thyroid hormone (RTH) is usually dominantly inherited and is characterized by elevated free thyroid hormones in the serum and failure to suppress pituitary thyroid stimulating hormone (TSH) secretion with variable refractoriness to hormone action in peripheral tissues. Two major forms of the disorder are recognized: asymptomatic individuals with generalized resistance (GRTH) and patients with thyrotoxic features, suggesting predominant pituitary resistance (PRTH). Molecular genetic analyses indicate that both GRTH and PRTH are associated with diverse mutations in the thyroid hormone receptor beta gene, which localize to three regions in the hormone binding domain of the receptor. In addition to being functionally impaired, the mutant receptors are also able to inhibit their wild-type counterparts in a dominant negative manner. Recognized features of RTH include failure to thrive, growth retardation and attention-deficit hyperactivity disorder in childhood, and goitre and thyrotoxic cardiac symptoms in adults. The pathogenesis of variable tissue resistance is not fully understood but may be related to the differing tissue distributions of a and b thyroid hormone receptors and variable dominant negative activity of mutant receptors on different target genes.



http://www.ncbi.nlm.nih.gov/pubmed/15611821?ordinalpos=12&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[Thyroid hormone resistance syndrome][Article in Portuguese]


Carvalho GA, Ramos HE.
Serviço de Endocrinologia e Metabologia, Universidade Federal do Paraná, Curitiba, PR. carvalho@mais.sul.com.br

Resistance to thyroid hormone (RTH) is a syndrome characterized by elevated serum thyroid hormone (TH) levels and elevated or inappropriately normal thyrotropin levels. In general, patients exhibit TH resistance in the pituitary and peripheral tissues. The phenotype of RTH is variable; the affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation, the variable hyposensitivity to TH among individuals as well as in different tissues. In almost all cases the genetic basis of RTH lies in mutation of the carboxyl-terminus of the ss-thyroid hormone receptor. RTH is a dominant disorder, except in one family; most individuals are heterozygous for the mutant allele. New standard techniques and genetically engineered mouse model systems have increased our understanding on TH receptor action, in particular, how mutant thyroid receptors from RTH patients can block wild-type thyroid receptor function (dominant negative activity), and how the mutant receptors can differently affect various tissues and individuals.



http://www.ncbi.nlm.nih.gov/pubmed/8594618?ordinalpos=14&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Syndrome of resistance to thyroid hormone: insights into thyroid hormone action.Kopp P, Kitajima K, Jameson JL.
Division of Endocrinology, Metabolism, and Molecular Medicine, Northwestern University Medical School, Chicago, Illinois 60611, USA.

Thyroid hormones (T3, T4) exert multiple cellular effects through nuclear thyroid hormone receptors (TR alpha, TR beta). Thyroid hormone receptors are transcription factors that act by altering patterns of gene expression. Resistance to thyroid hormone (RTH) is a rare disorder caused by mutations in the TR beta gene. Biochemically, the syndrome is defined by elevated circulating levels of free thyroid hormones due to reduced target tissue responsiveness and normal, or elevated, levels of thyroid-stimulating hormone (TSH). This "inappropriate" TSH elevation contrasts with the situation in hyperthyroidism, where the pituitary secretion of TSH is suppressed. Patients with RTH usually present with goiter and an euthyroid or mildly hypothyroid metabolic state. Thus, pituitary resistance results in hypersecretion of TSH, which compensates, at least in part, for hormone resistance in peripheral tissues. Despite this compensation, clinical effects of RTH can include short stature, delayed bone maturation, hyperactivity, learning disabilities, and hearing defects, as well as variable features of hyper- and hypothyroidism. With the exception of a single sibship, which harbored a deletion of the entire coding sequence of the TR beta gene and a recessive pattern of inheritance, all other cases of RTH have been inherited in an autosomal dominant manner or have been de novo heterozygous mutations of the TR beta gene. The dominant pattern of inheritance is explained by the functional properties of the mutant receptors which act in a dominant negative manner to block the activity of normal TR alpha and TR beta receptors. Now that a large number of different RTH mutations have been identified, it is striking that the mutations are clustered within restricted domains in the carboxyterminal region of the receptor. Mutations in these regions have been shown to preserve critical receptor functions such as dimerization and DNA binding, while inactivating other activites such as T3 binding and transcriptional activation. The examination of patients with RTH and their mutated receptors has provided important insights into the mechanisms of thyroid hormone action, the structure-function relationship of the receptors, and the molecular mechanisms of dominant negative activity.


http://www.ncbi.nlm.nih.gov/pubmed/7998483?ordinalpos=15&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Resistance to thyroid hormone--an uncommon cause of thyroxine excess and inappropriate TSH secretion.Chatterjee VK.
Department of Medicine, University of Cambridge, Addenbrooke's Hospital, United Kingdom.

Resistance to thyroid hormone (RTH) is an uncommon inherited cause of hyperthyroxinemia with inappropriate TSH secretion. The syndromes are characterized by reduced target tissue responsiveness to circulating free thyroid hormones. The differential diagnosis to other diseases with similar laboratory results (high T4 with normal TSH) like familial dysalbuminemia or antibodies against iodothyronines or TSH is now possible with the appropriate use of new assays for free thyroid hormones. In the presence of thyrotoxic symptoms it may be difficult to differentiate the syndrome from a TSH-secreting pituitary tumour. Familial occurrence and a normal TSH-response to TRH that can not be suppressed by T3 are characteristic features of RTH, that may be helpful in that respect. The majority of RTH cases are dominantly inherited and have highly variable clinical signs and symptoms. There are, however, mainly two forms of the syndrome that have been shown to overlap clinically and biochemically, namely a generalised resistance (GRTH) and a more "selective" pituitary resistance to thyroid hormones (PRTH). The absence of thyrotoxic symptoms rather suggests GRTH, whereas thyrotoxic signs seem to be characteristic for PRTH. Following the cloning of thyroid hormone receptors, familial GRTH was shown to be tightly linked to the TR-(Thyroid hormone receptor)-beta gene locus. Molecular genetic studies have shown that even within a single kindred the same receptor mutation was associated with both, GRTH or PRTH, and therefore suggest that these two forms represent part of a variable clinical spectrum of a single genetic disorder.


http://www.ncbi.nlm.nih.gov/pubmed/8954015?ordinalpos=1&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_DiscoveryPanel.Pubmed_RVAbstractPlus

Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor.Weiss RE, Hayashi Y, Nagaya T, Petty KJ, Murata Y, Tunca H, Seo H, Refetoff S.
Department of Medicine, University of Chicago, Illinois 60637, USA. rweiss@medicine.bsd.uchicago.edu

Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. To date, all individuals expressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor beta (TR beta) gene that impair T3-mediated function. We describe a unique family in which the dominantly inherited RTH is not associated with abnormalities in the TR beta or TR alpha genes, as determined by gene sequencing and linkage analysis. However, affected family members manifest a severe form of RTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8- to 10-fold the normal replacement doses of L-T4 and L-T3. No other endocrine abnormalities were detected. The defect developed de novo in the proposita and was transmitted to her two children of unrelated fathers. As cultured fibroblasts from the proposita responded poorly to T3 despite a normal concentration of TR, other abnormalities in the mediation of T3 action were sought. Nucleotide sequences of the TSH beta promoter, containing thyroid hormone response elements, and TR-interacting protein 1 were normal. Nuclear extracts (NE) of cultured skin fibroblasts from affected individuals of this family were tested for their interaction with normal TR beta and thyroid hormone response elements by the electrophoretic mobility shift assay. NE from the proposita showed a strong additional band compared to NEs from normal individuals and patients with RTH caused by TR beta mutations or deletion. Far Western analysis of NE from the affected daughter hybridized with labeled TR beta demonstrated an additional band that was not seen in NEs from a normal control or patients with TR beta gene defects. It is concluded that the etiology of RTH is not confined to abnormalities in the TR beta gene. An abnormal cofactor with a specific function in the regulation of thyroid hormone action is probably involved in the expression of the RTH phenotype in this family.



http://www.ncbi.nlm.nih.gov/pubmed/15860414?ordinalpos=18&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Thyroid hormone receptor mutations and disease: beyond thyroid hormone resistance.Cheng SY.
Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA. sycheng@helix.nih.gov

Thyroid hormone receptors (TRs) are ligand-dependent transcription factors that mediate the biological activities of thyroid hormone (T3). Two THR genes (A and B), located on different chromosomes, yield four T3-binding isoforms with highly conserved sequences in the DNA- and ligand-binding domains. Mutations of THRB cause a human genetic disease, thyroid hormone resistance syndrome (RTH). Comprehensive genomic profiling unveiled the contribution of novel change-of-function mutations of TRbeta to the pathogenesis of RTH. In addition, abnormalities associated with mutations of the THRA gene have been uncovered recently. The phenotypic manifestations of mutated THRB and THRA genes are distinct, indicating isoform-dependent actions of TR mutants in vivo. Therefore, mutant TRs provide a new paradigm to understand the molecular basis of receptor disease.



http://www.ncbi.nlm.nih.gov/pubmed/15543767?ordinalpos=19&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

[Familial generalized thyroid hormone resistance. Report of one case][Article in Spanish]


López JM, Jiménez M, Campino C.
Departamento de Endocrinología, Facultad de Medicina, Pontificia Universidad Católica de Chile. jmlopez@med.puc.cl

Thyroid hormone resistance is a rare autosomal dominant disease associated, in more than 90% of cases, to mutations in the beta thyroid hormone receptor. We report a 23 years old male that consulted for a psychiatric condition. Clinically, the patient was euthyroid in spite of high total and free T4 and T3 concentrations, while TSH remained normal. Also, TSH showed a five fold increase under TRH stimulation. The mother and one of his brothers had the same pattern of abnormal serum thyroid hormones. We discuss the diagnostic considerations and the protocol to study this rare pathology.



http://www.ncbi.nlm.nih.gov/pubmed/8954015?ordinalpos=20&itool=EntrezSystem2.PEntrez.Pubmed.Pubmed_ResultsPanel.Pubmed_RVDocSum

Dominant inheritance of resistance to thyroid hormone not linked to defects in the thyroid hormone receptor alpha or beta genes may be due to a defective cofactor.Weiss RE, Hayashi Y, Nagaya T, Petty KJ, Murata Y, Tunca H, Seo H, Refetoff S.
Department of Medicine, University of Chicago, Illinois 60637, USA. rweiss@medicine.bsd.uchicago.edu

Resistance to thyroid hormone (RTH) is an inherited syndrome of reduced tissue responsiveness to thyroid hormone. To date, all individuals expressing the RTH phenotype have been found to harbor mutations in the thyroid hormone receptor beta (TR beta) gene that impair T3-mediated function. We describe a unique family in which the dominantly inherited RTH is not associated with abnormalities in the TR beta or TR alpha genes, as determined by gene sequencing and linkage analysis. However, affected family members manifest a severe form of RTH, with reduced responses of thyrotrophs and peripheral tissues requiring 8- to 10-fold the normal replacement doses of L-T4 and L-T3. No other endocrine abnormalities were detected. The defect developed de novo in the proposita and was transmitted to her two children of unrelated fathers. As cultured fibroblasts from the proposita responded poorly to T3 despite a normal concentration of TR, other abnormalities in the mediation of T3 action were sought. Nucleotide sequences of the TSH beta promoter, containing thyroid hormone response elements, and TR-interacting protein 1 were normal. Nuclear extracts (NE) of cultured skin fibroblasts from affected individuals of this family were tested for their interaction with normal TR beta and thyroid hormone response elements by the electrophoretic mobility shift assay. NE from the proposita showed a strong additional band compared to NEs from normal individuals and patients with RTH caused by TR beta mutations or deletion. Far Western analysis of NE from the affected daughter hybridized with labeled TR beta demonstrated an additional band that was not seen in NEs from a normal control or patients with TR beta gene defects. It is concluded that the etiology of RTH is not confined to abnormalities in the TR beta gene. An abnormal cofactor with a specific function in the regulation of thyroid hormone action is probably involved in the expression of the RTH phenotype in this family.




http://jcem.endojournals.org/cgi/reprint/86/11/5142?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=5000&resourcetype=HWCIT


http://jcem.endojournals.org/cgi/reprint/84/9/3099?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=5000&resourcetype=HWCIT

http://jcem.endojournals.org/cgi/content/full/84/2/401?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=5000&resourcetype=HWCIT


http://jcem.endojournals.org/cgi/reprint/84/11/3919?maxtoshow=&HITS=10&hits=10&RESULTFORMAT=&searchid=1&FIRSTINDEX=0&minscore=5000&resourcetype=HWCIT

http://jcem.endojournals.org/cgi/reprint/84/2/401

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