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About Reverse T3 and Reverse T3 Dominance The thyroid gland is located in the lower part of the neck near the mans Adam’s Apple. It secretes two essential thyroid hormones: triiodothyronine (T3) and thyroxine (T4) which are responsible for regulating cell metabolism in every cell in your body. They promote optimal growth, development, function and maintenance of all body tissues. They are also critical for nervous, skeletal and reproductive tissue as well as regulating body temperature, heart rate, body weight and cholesterol. In a healthy patient a normal thyroid gland secretes all of the circulating T4 (about 90 to 100mcg daily) and about 20% of the circulating T3. The T4 made by the thyroid gland circulates throughout the body and is converted by the 5-deiodinase enzymes Type 1 & 2 into T3 or via the 5-deiodinase Type 3 enzymes into reverse T3 in roughly equal amounts of T3. Most of the biological activity of thyroid hormones is due to T3. It has a higher affinity for thyroid receptors and is approximately 4 times more potent than T4. Because 80% of serum T3 is derived from T4 in tissues such as the liver and kidney, T4 is considered a pro-hormone. No receptors have ever been identified for T4. Normal physiological production ratio of T4 to T3 is 3.3:1. Reverse T3 (rT3) is virtually inactive having only 1% the activity of T3 and being a T3 antagonist binds to T3 receptors blocking the action of T3 and thus acting as a metabolic break. Normal metabolism of T4 requires the production of the appropriate ratio, or balance, of T3 to rT3. If the proportion of rT3 dominates then it will antagonize T3 thus producing hypothyroid symptoms despite sufficient circulating levels of T4 and T3. Reverse T3 has the same molecular structure as T3 however its three dimensional arrangement (stereochemistry) of atoms is a mirror image of T3 and thus fits into the receptor upside down without causing a thyroid response and thus preventing or antagonizing the active T3 from binding to the receptor acting as a metabolic break. Reverse T3 dominance,  also known as Wilson’s Syndrome, is a condition that exhibits most  hypothyroid symptoms  although circulating levels of T3 and T4 are within normal test limits. The metabolism of T4 into rT3 is in excess when compared to T3 therefore it is a T4 metabolism malfunction rather than a straight forward thyroid deficiency. Periods of prolonged stress may cause an increase in cortisol levels as the adrenal glands respond to the stress. The high cortisol levels inhibit the 5-deiodinase enzyme Type 1 and thus the conversion of T4 into T3 thus reducing active T3 levels. The conversion of T4 is then shunted towards the production of the inactive rT3 via the 5-deiodinase enzyme Type 3. This rT3 dominance may persist even after the stress passes and cortisol levels have returned to normal as the rT3:T3 imbalance itself may also inhibit the 5-deiodinase enzyme Type 1 thus perpetuating the production of the inactive rT3 isomer. There is some argument to this last point with some research indicating that the elevated rT3 is only temporary and not a permanent condition and in most healthy people this may well be the case. We have however found that in many patients suffering from a range of hypothyroid symptoms do indeed have prolonged elevated rT3 levels which respond favorably to this treatment. Many medical practitioners do not accept rT3 dominance theory and thus many doctors will refuse to treat this condition despite the fact many suffers have been successfully treated. See below for the evidence in the references. Other causes of reverse T3 dominance include: leptin resistance, inflammation (NF kappa-B), dieting, nutrient difficiencies such as low iron, selenium, zinc, chromium, Vit B6 and B12, Vit D and iodine, Low testosterone, low human growth hormone, Insulin dependent Diabetes, Pain, Stress, environmental toxins, Free radical load, Hemorrhagic shock, Liver disease, Kidney disease, Severe or systemic illness, severe injury, Surgery, Toxic metal exposure. Diagnosis In addition to considering T3 levels we also need to consider rT3 because if it is too high it will block the effects of T3 thus producing hypothyroid symptoms. If this is the case the TSH, T4 and T3 tests alone will give a false impression of true thyroid function and therefore you must also measure rT3 in order to diagnose this condition. Ideally the ratio of T3/rT3 multiplied by 100 should be between 1.06 to 2.2 – preferably towards the upper end of this range. If this ratio is at the low end of this range or below then rT3 dominance is present and slow release T3 therapy needs to be initiated once adrenal exhaustion, hypoglycemia, nutritional deficiencies and/or low sex hormone levels have been ruled out and/or treated as they can all inhibit 5-deiodinase Type 1 activity. In addition nutrients such as selenium, zinc, Vit B6, B12 and E, iron and iodine should be supplemented as they are necessary cofactors for this enzyme to function correctly and thus ensure appropriate T3 production. It is also very important that if elevated levels of cortisol are found (stage 1 adrenal exhaustion) it should be treated first because if it remains elevated it will only continue to inhibit the 5-deiodinase enzyme and thus continue rT3 production reducing the effectiveness of this treatment. Low cortisol levels should also be treated because low cortisol will reduce the number of T3 receptors and also prevent T3 transport within the cell, again impeding improvement while on this treatment. In addition some patients respond poorly to thyroid medication if adrenal fatigue is present. Therefore we recommend you test adrenal function and correct it before commencing this treatment. In summary you should have the following tested: DHEA, cortisol, TSH, T3, T4 and reverse T3. Treatment It is important that NO  T4 is supplemented as it will only be converted into rT3 and perpetuate the viscous cycle. For information on how to treat rT3 dominance contact your doctor or alternatively you are required to access our online consultations . Adrenals  are also addressed to make sure both DHEA and cortisol levels are within the optimal range to ensure they are not affecting conversion. Testosterone and hGH levels may also need adjusting. Additional Information Refer to our Hyopthyroidism Information page. REFERENCES Peripheral Metabolism of Thyroid Hormones: A Review .  Alternative Medicine Review, August, 2000 by Greg KellyUnder normal conditions, 45-50 percent of the daily production of T4 is transformed into rT3. Substantial individual variation in these percentages can be found secondary to a range of environmental, lifestyle, and physiological influences[1] Although an adequate understanding of the metabolic role of rT3 is somewhat limited, it is thought to be devoid of hormonal activity and to act as the major competitive inhibitor of T3 activity at the cellular level.[2] Experimental data also suggests rT3 has inhibitory activity on 5′-deiodinase,[3] suggesting it might also directly interfere with the generation of T3 from T4.[1.] Chopra IJ. An assessment of daily production and significance of thyroidal secretion of 3,3′,5′ triiodithyronine (reverse T3) in man. J Clin Invest 1976:58:32-40.[2.] Robbins J. Factors altering thyroid hormone metabolism. Environ Health Perspect 1981;38:65-70.[3.] Kohrle J, Spanka M, Irmscher K, Hesch RD. Flavonoid effects on transport, metabolism and action of thyroid hormones. Prog Clin Biol Res 1988;280:323-340. A study of extrathyroidal conversion of thyroxine (T4) to 3,3’,5-triiodothyronine (T3) in vitro.   Endocrinology;101(2):453-63. Chopra IJ Many endocrinologists believe that reverse T3 (3,3’,5-triodothyronine) is only an inactive metabolite with no physiologic effect. This is an erroneous belief as this and other studies demonstrate that reverse T3 (rT3) is a more potent in­hibitor of T4 to T3 conversion than propylthiouracil (PTU) which is a medication used to decrease thyroid function in hyperthyroidism. In fact, rT3 is 100 times more potent than PTU at reducing T4 to T3 conversion. Clearly demonstrating that rT3 not just an inactive metabolite, but rather a potent inhibitor of tissue thyroid levels. The authors conclude, “ Reverse t3 appeared to inhibit the conversion of t4 to T3 with a potency which is about 100 times more than PTU …” Thyroid Hormone Concentrations, Disease, Physical Function and Mortality in Elderly Men.  The Journal of Clinical Endocrinology & Metabolism 2005; 90(12):6403–6409. Annewieke W. van den Beld, Theo J. Visser, Richard A. Feelders, Diederick E. Grobbee, and Steven W. J. Lamberts Department of Internal Medicine , University Medical Center Utrecht, 3508 GA Utrecht, The Netherlands This study of 403 men investigated the association between TSH, T4, free T4, T3, TBG and reverse T3 (rT3) and parameters of physical functioning. This study demonstrates that TSH and/or T4 levels are poor indicators of tissue thyroid levels and thus, in a large percentage of patients, cannot be used to determine whether a person has normal thyroid levels at the tissue level. This study demonstrates that rT3 inversely correlates with physical performance scores and that the T3/rT3 ratio is currently the best indicator of tissue levels of thyroid. This study showed that increased T4 and RT3 levels and decreased T3 levels are associated with hypothyroidism at the tissue level with diminished physicial func­tioning and the presence of a catabolic state (breakdown of the body). Low T3 syndrome, with low T3 and high reverse T3, is almost always missed when using standard thyroid function tests, as the T3 level is often in the low normal range and reverse T3 is the high normal range, again making the T3/rT3 ratio the most useful marker for tissue hypothyroidism and as a marker of diminished cel­lular functioning. The authors of this study conclude, “S ubjects with low T3 and high reverse T3 had the lowest PPS [PPS is a scoring system that takes into account normal activities of daily living and is a measure of physical and mental function­ing]…Furthermore, subjects with high reverse T3 concentrations had worse physical performance scores and lower grip strength. These high rT3 levels were accompanied by high FT4 levels (within the normal range)…These changes in thyroid hormone concentrations may be explained by a decrease in peripheral thyroid hormone me­tabolism… Increasing rT3 levels could then represent a catabolic state, eventually proceeding an overt low T3 syndrome.” This study demonstrates that TSH and T4 levels are poor measures of tissue thyroid levels, TSH and T4 levels should not be relied upon to determine the tissue thyroid levels and that the best estimate of the tissue thyroid effect is the rT3 level and the T3/rT3 ratio. “Elevation in reverse triiodothyronine level is also seen as a consequence of diminished use of thyroxine, diminished thyroxine-to-triiodothyronine conversion, and diminished tissue levels of triiodothyronine. And “obtaining free triiodothyronine, reverse triiodothyronine, and triiodothyronine/reverse-triiodothyronine ratios may help obtain a more accurate evaluation of tissue thyroid status and may be useful to predict those who may respond favorably to triiodothyronine supplementation” Erika T. Schwartz, MD, Kent Holtorf, MD, Hormones in Wellness and Disease Prevention: Common Practices, Current State of the Evidence, and Questions for the Future. Prim Care Clin Office Pract 35 (2008) 669–705

Written by: Berenike Rogge , Marcus Heldmann , Krishna Chatterjee , Carla Moran , Martin Göttlich , Jan Uter , Tobias A. Wagner-Altendorf , Julia Steinhardt , Georg Brabant , Thomas F. Münte  & Anna Cirkel   Thyroid Research volume 16 , Article number: 34 (2023) Abstract Background Being critical for brain development and neurocognitive function thyroid hormones may have an effect on behaviour and brain structure. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. Methods High-resolution 3D T1-weighted images were acquired in 21 patients with a resistance to thyroid hormone ß (RTHß) in comparison to 21 healthy matched-controls. Changes in grey and white matter, as well as cortical thickness were evaluated using voxel-based morphometry (VBM) and diffusion tensor imaging (DTI). Results RTHß patients showed elevated circulating fT4 & fT3 with normal TSH concentrations, whereas controls showed normal thyroid hormone levels. RTHß patients revealed significantly higher scores in a self-rating questionnaire for attention deficit hyperactivity disorder (ADHD). Imaging revealed alterations of the corticospinal tract, increased cortical thickness in bilateral superior parietal cortex and decreased grey matter volume in bilateral inferior temporal cortex and thalamus. Conclusion RTHb patients exhibited structural changes in multiple brain areas. Whether these structural changes are causally linked to the abnormal behavioral profile of RTHß which is similar to ADHD, remains to be determined. Introduction Thyroid hormone levels and transporter proteins influence the development of the human brain. Brain development is mediated by thyroid hormone action [ 1 ]. Irregularities in balance of thyroid hormones at precise developmental timings can lead to somatic and cognitive changes [ 2 ]. We have previously shown that a period of only several weeks duration of induced hyper- or hypothyroid states influences the function and structure of the brain, without significant measurable somatic changes in parameters such as heartrate or blood pressure [ 3 , 4 , 5 , 6 ]. Moreover, hypothyroidism during adulthood induces morphological changes in the brain [ 7 ]. Thyroid hormones regulate developmental and physiological processes, acting via nuclear, thyroid hormone receptors (TRa, TRb), to alter transcription of target genes. Mutations in receptor genes ( THRB and THRA ), cause syndromes of Resistance to Thyroid hormone (RTHb, RTHa) [ 8 , 9 ], whose phenotypes differ due to the differential expression of TR isoforms in tissues (TRα1: central nervous system, myocardium, skeletal muscle, bone and gastrointestinal tract; TRβ1: liver, kidney; TRβ2: hypothalamus, pituitary, cochlea, retina) [ 10 ]. RTHβ, due to heterozygous mutations in THRB , is a relatively uncommon disorder with over 800 families with 200 different receptor mutations being recorded to date [ 11 ]. Due to impaired function of the TRβ2 isoform expressed in the hypothalamus and pituitary [ 12 ], normal negative feedback regulation of TSH by thyroid hormones is perturbed, resulting in raised circulating free thyroid hormones (fT4, fT3) with non-suppressed TSH concentrations [ 10 ]. Due to differential distribution of TR subtypes, RTHβ patients exhibit symptoms reflecting hypo- and hyperthyroid states of specific tissues [ 10 ]. Typical phenotypes in RTHβ include goiter, resting tachycardia, recurrent ear infections in childhood causing hearing loss, altered photoreceptor function and attention-deficit hyperactivity disorder (ADHD) [ 13 , 14 , 15 ]. Indeed, previous studies suggest that ADHD is the main neurocognitive abnormality in RTHβ, with approximately half of RTHβ patients exhibiting an ADHD-like phenotype [ 16 , 17 , 18 , 19 ]. The differential tissue distribution of TRs suggests that RTHß patients might show abnormalities in brain structure, which, in turn, might be related to behavioural changes. Accordingly, in this study, changes in grey matter volume using voxel based morphometry, were analyzed [ 20 , 21 ]. Previous studies of patients in hyper- or hypothyroid states [ 3 , 7 , 22 , 23 ], have revealed structural changes, suggesting that this method would also reveal changes in RTHß. Measurement of cortical thickness has also highlighted structural changes in thyroid disease [ 24 , 25 ]. An earlier publication had suggested that male RTHb patients exhibit multiple Heschl’s transverse gyri in the primary auditory cortex [ 26 ], so we sought to verify these findings in the current study. Thyroid hormones have been shown to regulate myelination of neurons [ 1 ]. Such changes in myelination in brain white matter are reflected in different parameters gleaned from diffusion tensor imaging (DTI). For example, reductions of fractional anisotropy (FA) have been found in hypothyroid patients in the corticospinal tract, the posterior limb of the internal capsule, uncinate fasciculus, and inferior longitudinal fasciculus [ 27 ]. Our exploratory study aimed to delineate the influence of mutations in the thyroid hormone receptor (TR) ß gene on brain structure. Materials and methods Subjects In total forty-two subjects were recruited; twenty-one RTHβ subjects (mean age 39 y, SD 15.0, 12 women) were matched with 21 healthy controls (mean age 38 y, SD 14.0, 12 women, from Lübeck, Germany). The participants in this study are unselected cases of RTHb, diagnosed in Cambridge following referral to this centre for investigation of discordant thyroid function (raised thyroid hormones, non-suppressed TSH). The investigation of all participants took place at the University Medical Centre Schleswig-Holstein, Campus Lübeck, Germany. The patients carried the following heterozygous TRß mutations: R320H (n = 5), R438H (n = 4), R429Q (n = 3), R383C (n = 2), M310V (n = 1), G345C (n = 1), P453S (n = 1), R243W (n = 1), T277I (n = 1), R338W (n = 1), E460K (n = 1). Mutations were maternally (n = 12) or paternally (n = 3) inherited or occurred de novo  (n = 6). Medication in single patients included thyroxine for coincident autoimmune hypothyroidism (n = 1), propranolol in reduced dosage at initial referral, alfacalcidol for postsurgical hypoparathyroidism and atenolol for high blood pressure. All patients were screened for general health, drug abuse and medical comorbidities, with evaluation of thyroid status (TSH, fT4, fT3), and fasting lipid profiles (Total, LDL and HDL cholesterol). All patients were examined by an endocrinologist. Their structural brain images were evaluated and approved to be normal by a neuroradiologist. All subjects were right-handed. Blood parameters were analysed on serum (transported at minus 80) in Cambridge with TSH, fT3 and fT4 being measured by Advia Centaur (Siemens) as described previously [ 28 ]. The reference ranges of hormone measurements were as follows: fT3 3.5–6.5 pmol/l, fT4 10–19.8 pmol/l and TSH 0.35–5.5 mU/l. Attention deficit analysis We used the Adult ADHD Self-Report Scale  (ASRS-v1.1) [ 29 ], composed of 18 questions describing typical symptoms of ADHD consistent with the Diagnostic and Statistical Manual of Mental Disorders (DSM) criteria. The test asks for typical symptoms (i.e. deficits in attention, concentration), impairments (i.e. at work, school or in family settings) and history (i.e. were the symptoms also present in childhood). Additionally, the ADHD Rating Scale-IV  was used, consisting of two subscales including 9 items scaling inattention and 9 items regarding hyperactivity impulsivity [ 29 ]. To test for group differences independent t-test per ADHD Rating Scale-IV  subscales will be used. MRI data acquisition and analysis Structural MR imaging was performed at the CBBM Core Facility Magnetic Resonance Imaging using a 3-T Siemens Magnetom Skyra scanner equipped with a 64-channel head-coil. Structural images of the whole brain were recorded using a 3D T1-weighted MP-RAGE sequences were acquired (TR = 1900 ms; TE = 2.44 ms; TI = 900 ms; flip angle 9°; 1 × 1 × 1 mm3 resolution; 192 × 256 × 256 mm3 field of view; acquisition time 4.5 min). Diffusion-weighted data were recorded using a 64-direction DTI sequence (Single-Shot EPI sequence, 70 slices, TR = 6100 ms, TE = 116 ms, FOV 244 × 244 mm2, voxel size 1 × 1 × 2 mm3, flip angle 90, b-value 1500 s/mm2, one b0 (without diffusion weighting) image at the beginning and 4 b-zero images at the end of the sequence). Analysis was corrected for age and gender. Diffusion tensor imaging Diffusion tensor imaging (DTI) is an imaging technique enabling to non-invasively measure white matter changes in the central nervous system. Preprocessing including eddy correction and rotation of the vector definitions was performed using the FMRIB Software Library [ 30 ]. The resulting tensor images were transformed to DTI-ToolKit data format ( http://www.nitrc.org/projects/dtitk/ ) and registered to the IIT tensor template provided by the IIT atlas [ 31 ] combining rigid, affine, and diffeomorphic registration steps. Based on the spatially normalized tensor images DTI-ToolKit was also taken to calculate individual FA maps. To test for group differences SPM12 toolbox was used to perform a two-sample t-test with age as covariate. Statistic images were assessed for cluster-wise significance using a cluster-defining threshold of P = 0.001; the 0.05 FWE-corrected critical cluster size was 275. Voxel based morphometry Voxel-based morphometry (VBM) is a technique to analyses structural changes of the brains grey matter using T1-weighted MR images. It measures differences of grey matter by a voxel-wise comparison of multiple brain images. VBM analysis was evaluated in the whole brain, carried out using Statistical Parametric Mapping 12b (SPM, http://www.fil.ion.ucl.ac.uk/spm ) and Computational Anatomy Toolbox ( http://www.neuro.uni-jena.de/cat/ ; version 12.6, 1445) in Matlab R2019b. Preprocessing of the data comprised tissue segmentation and spatial registration using DARTEL, removal of inhomogeneities and noise, global intensity normalization and spatial smoothing (12 mm FWHM Gaussian Kernel). Total intracranial volume (TIV) was also calculated. After preprocessing a two-sample t-test was computed as group statistic for every voxel, whereby age and intracranial volume were considered as confounding factors. Since we found no significant differences when applying a correction for multiple testing, we considered the results also at an uncorrected p-value of 0.001, which is a common method to explore patient data. Due to an increase of the alpha error it has to be acknowledged, though, that this approach may produce false positive results. Cortical thickness Cortical thickness analysis measures the width of grey matter in the human cortex. The analysis of cortical thickness was also performed with SPM12 and the CAT toolbox using the algorithm described by Dahnke et al. [ 32 ]. Based on the VBM preprocessing steps the central surface and the cortical thickness was estimated using a projection based thickness approach [ 32 ]. Initial surface reconstruction was followed by repair of topological defects and surface refinement resulting in the final central mesh [ 33 ]. For statistical analysis we followed the program’s recommendation using a 15 mm FWHM Gaussian kernel for spatial smoothing. We calculated a two-sample t-test with age as covariate. To correct for multiple comparisons at cluster level = 633 a threshold of p = 0.05 (FWEc) and a cluster defining threshold of p = 0.001 was applied. Relationship brain structure and attention deficit To test for a correlational relationship between structural changes and Attention deficit test scores regions of interest (ROIs) will be defined by the clusters resulting from the group comparisons. Mean FA and VBM scores extracted from these clusters will be correlated with test scores which also show a significant difference between groups. Since CAT toolbox does not allow for the individual definition of ROIs mean values will be extracted from the atlas definition in which the significant group difference was observed. The atlas definition used here was the Desikan-Killiany Atlas. Correlations were calculated using spearman’s rho. Since the correlational analysis was exploratory we did not correct for multiple comparisons. Analysis of Heschl’s gyri The sizes of Heschl’s gyri were measured manually, the brain region was selected by specialists voxel by voxel. The program mricron ( https://www.nitrc.org/projects/mricron  [ 34 ] was used to define the region layer-by-layer with manual tracing using a mouse-guided cursor. Heschl’s gyri analysis was performed in a blinded fashion, first in independent sessions, followed by a subsequent combined session by two different examiners (one neurologist, one neuroscientist). In line with previous reports number of Heschl’s gyri was classified into typical (one gyrus) and atypical (multiple gyri) [ 26 , 35 , 36 ]. Prior to performing the analyses, the examiners agreed to the procedures during a joint session using sample brain images. Differences between the number of typical and atypical Heschl’s gyri were statistically tested using a chi squared test. Results Circulating thyroid hormone concentrations Mean TSH was shown to be within the normal range in both RTHβ patients and control subjects. Both fT4 (RTHβ: Mean 28.4 pmol/L, SD 5.5 pmol/L. Controls: Mean: 14.6 pmol/L, 1.6 pmol/L. P < 0.001, two-sample t-test) and fT3 (RTHβ: Mean 8.6 pmol/L, SD 1.6 pmol/L. Controls: 5.1 pmol/L, SD 0.5 pmol/L. P < 0.001, two-sample t-test) concentrations were significantly elevated in RTHβ patients, but were within the normal range in control subjects. Clinical symptoms All subjects were examined by an endocrinologist and a neurologist with additional training in psychiatry. Out of the 21 RTHβ patients, one showed tachycardia, whereas eleven reported occasional palpitations. In the clinical history, 9 patients reported difficulties in concentrating and 12 reported anxiety episodes. Other signs and symptoms of hyperthyroidism (increased perspiration, peripheral tremor, proximal myopathy, increased stool frequency, weight loss, changes in menstrual cycle) were not present. None of the patients exhibited features of hypothyroidism (e.g. cold intolerance, constipation, weight gain, dry skin, hair loss, bradycardia, delayed relaxation of tendon reflexes, carpal tunnel syndrome). Attention deficit analysis The self-rating questionnaires for ADHD I and II revealed significantly higher scores in the RTHβ group (ADHD I mean = 95.7 (9.1), ADHD II mean = 36.1 (2.3)) in comparison to controls (ADHD I mean = 60.6 (4.8), ADHD II mean = 24.1 (1.7); ADHD I: RTHβ vs. controls t(36)=|3.31|, p = 0.002; ADHD II: RTHβ vs. controls t(36)=|4.16|, p = 0.0018). Imaging results Tractography via diffusion tensor imaging (DTI) revealed significantly higher FA in the corticospinal tract (CST) in RTHß patients (FWEc 0.05, k = 275) (see Fig.  1 ; Table  1  A). In the RTHβ group, superior parietal cortical thickness was increased bilaterally (FWE(p < 0.05), k = 587) (see Fig.  2  and Table  1 B). Voxel-based morphometry (VBM) revealed decreased grey matter volume (GMV) bilaterally in the inferior temporal cortex and the thalamus and in the right superior frontal orbital gyrus in RTHβ subjects. Increase in GMV was shown in left precuneus and right middle frontal gyrus in RTHβ subjects. VBM results were based on an uncorrected level (p[unc.] = 0.001, k = 100) (see Fig.  3 ; Table  1  C). Analysis of Heschl’s gyri showed no statistical difference when comparing patients and controls (Chi2(2) = 4.40; p = 0.11). Similar to published literature [ 26 ], we also checked for gender differences in this structural parameter, finding that women in the RTHβ-group had multiple Heschl’s gyri less often than female controls (Chi2(2) = 7.6, p = 0.02, see Table  2 ); for men there was no significant difference in Heschl’s gyri (Chi2(2) = 0.47, p = 0.78). Relationship brain structure and attention deficit analysis With regard to VBM analyses the cluster located in the right midfrontal cortex was significantly correlated with ADHD I (rho = 0.66, p = 0.002) and ADHD II (rho = 0.58, p = 0.009) scores in the RTHβ-group, whereas the control group showed no significant correlation. Furthermore, in the RTHβ-group, decreases in FA values in the right CST were marginally correlated with the ADHD I (rho=-0.4, p = 0.091) and ADHD II (rho = 0.41, p = 0.083) scores. In contrast, FA values in the left CST were positively correlated with ADHD II scores (rho = 0.43, p = 0.046) in the control group (see Fig.  4 ). Analysis of the cortical thickness ROIs revealed no significant relationship. Discussion As anticipated, RTHß patients showed significant differences in both grey and white matter compared to normal control participants and these changes will be considered in further detail as follows. Diffusion tensor imaging showed that FA in the corticospinal tract differed in RTHß versus control subjects. The corticospinal tract supports motor control of the spinal cord and voluntary movement [ 37 ]. It is known that thyroid hormones regulate myelin formation [ 1 ], therefore it can be speculated that a changed FA in RTHß can be due to their local hyperthyroid state in the brain influencing white matter tissue and myelin formation. However, the functional relevance of these changes in the corticospinal tract remains to be explored using (for example) transcranial magnetic stimulation and sensitive measures of motor performance. Changes in white matter have been recorded in hyperthyroid patients with thyroid opthalmopathy [ 38 ] and also in patients with Resistance to Thyroid Hormone due to mutations in TRa [ 39 ]. Thus, more studies are needed to explore the influence of TH on brain white matter. Voxel based morphometry revealed a decrease of grey matter volume bilaterally in the inferior temporal cortex and the thalamus. The thalamus is a key relay hub, making multiple connections to cortical and subcortical regions. It is also known to play an important role in selective attention, visual and auditory information [ 40 ]. The functional significance of these thalamic changes remains to be explored. The temporal lobe and its associated networks are involved in multiple cognitive domains, including auditory, vision, language, memory, and semantic processing [ 41 ]. This structural observation is particularly interesting, since our RTHß patients showed an ADHD-like phenotype, which characteristically involves neuropsychological deficits. In addition, heterozygous RTHb patients exhibit altered retinal photoreceptor function and sensitivity of color perception [ 15 ], and this may correlate with the fact that the inferior temporal cortex plays a key part in the visual pathway, including color perception [ 42 ]. In a previous study [ 3 ] we have analyzed healthy participants with experimentally-induced thyrotoxicosis, revealing an increase of grey matter volume in the posterior part of the cerebellum and a decrease of grey matter volume in the anterior part of the cerebellum. While these observations clearly differ from findings in this study, it has to be kept in mind that the effects of biochemical hyperthyroidism in RTHß patients may be more complex, depending on whether particular brain regions are in a relatively hypothyroid or hyperthyroid state, depending on whether they express mutant TRß or normal TRα. Experimentally-induced thyrotoxicosis also leads to an increased connectivity in temporal lobe structures, caused by an increased connectivity to the cognitive control network [ 43 ]. Such increased connectivity supports a role for thyroid hormones in regulating paralimbic structures, with increased degree centrality in the temporal pole being correlated with changes in observed depression scores [ 43 ]. This may facilitate prefrontal control over limbic areas, possibly explaining the successful use of thyroid hormones as an augmentation therapy for depression. Heschl’s gyrus analysis  showed no difference among groups regarding number of gyri. Whereas one previous study had shown an increased number of gyri in RTHß men [ 26 ], this was not replicated by our results. Instead, we found less multiple Heschl’s gyri in RTHß women. We conclude that there is no substantial influence of RTHß on Heschl’s gyrus morphology in our cohort of patients. Cortical Thickness  was increased in superior parietal cortex bilaterally in the RTHß group. It is well-known that the parietal cortex is involved in sensory, motor, and cognitive functions, especially regarding space-based and feature-based attention functions and working memory [ 44 ]. The parietal cortex is involved in the attention network, parietal cortices generate attention-related modulatory signals and parietal lesions can lead to profound attentional deficits, including visuo-spatial neglect, hereby preventing directing attention contralesionally [ 45 ]. ADHD is known to be associated with impairments in attention and with changes in fronto-parietal networks [ 46 ], which is relevant because RTHß patients, including participants in the current study, exhibit an ADHD-like phenotype [ 16 , 17 , 18 , 19 ]. Indeed, increased parietal cortical thickness has also been shown in adult subjects with conventional ADHD [ 47 , 48 ] whereas reduced cortical thickness was seen in children and adolescents with ADHD [ 49 , 50 , 51 ]. Since our study has documented increased parietal cortical thickness in RTHb, it is tempting to postulate that this structural change may be linked to attentional deficits and ADHD-like phenotype in the disorder. With the knowledge that hypothyroidism during development can also affect cortical thickness in various brain regions [ 25 ], it is conceivable that resistance to thyroid hormone action which is also a relative hypothyroid state, could have contributed to this morphological change. Limitations of our study include the relatively small sample size and thus reduced power to detect subtle changes in brain structure. Additionally, the study population was heterogeneous, as RTHb patients from UK were matched with healthy controls from Germany, with a possibility of confounding due to socio-economic and educational differences between the two groups. Nevertheless, we maintain that our study contributes new knowledge about brain structure in this disorder. 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Written by Tim I. M. Korevaar   Thyroid Research volume 11 , Article number: 5 (2018) Abstract Physiological changes necessitate the use of pregnancy-specific reference ranges for TSH and FT4 to diagnose thyroid dysfunction during pregnancy. Although many centers use fixed upper limits for TSH of 2.5 or 3.0 mU/L, this comment describeds new data which indicate that such cut-offs are too low and may lead to overdiagnosis or even overtreatment. The new guidelines of the American Thyroid Association have considerably changed recommendations regarding thyroid function reference ranges in pregnancy accordingly. Also a stepwise approach to interpreting these guidelines is discussed as well as the relevant role of FT4 in diagnosis. Background Thyroid physiology changes during pregnancy and this necessitates the use of pregnancy-specific reference ranges for TSH and FT4 in order to adequately diagnose gestational thyroid disease [ 1 ]. Currently, many centers use a reference range for TSH with an upper limit of 2.5 mU/l in the first trimester and 3.0 mU/l in the second or third trimester to diagnose subclinical and overt hypothyroidism. This is based on outdated international guidelines from the American Thyroid Association (2011), the Endocrine Society (2012) and the European Thyroid Association (2014) [ 2 , 3 , 4 ]. Although each of these guidelines recommend to calculate lab-specific reference ranges for TSH and FT4, many centers do not have such reference ranges available. Instead, most centers adhere to the former second recommendation which is that, in the absence of lab-specific reference ranges, fixed upper limits for TSH (2.5 mU/l in the first and 3.0 mU/l in the second and third trimester) can be used. However, recent studies have indicated that these cut-offs are too low and may lead to overdiagnosis and unnecessary treatment, or even overtreatment. Based on some important findings discussed below, the 2017 American Thyroid Association guidelines have updated the recommendations on the upper limit for TSH during pregnancy. Main text Various studies have demonstrated that with the use of fixed TSH upper limits, 8–28% of pregnant women have a TSH concentration that is considered too high [ 5 , 6 ]. These numbers are much larger than the roughly 3–4% that would have a too high TSH if population-based reference ranges would be used to define the upper limits for TSH. Medicalization of a group of women as large as 8–28% is unwarranted, unsustainable and likely to cause more harm than benefit. Further data indicate that the upper limit for TSH should be higher. By summarizing 14 studies that calculated population-based pregnancy-specific reference ranges for TSH and/or FT4, our group was able to show that in more than 90% of all studies, the upper limit for TSH was above 2.5 or 3.0 mU/l [ 7 ]. Moreover, the few studies performed in a population that was proven to be iodine sufficient report an upper limit for TSH of 4.04 and 4.34 mU/l [ 7 ], however, the effects of population iodine status on reference range values remains to be studied. Interestingly, a large randomized controlled trial that screened approximately 100.00 pregnant women for subclinical hypothyroidism and hypothyroxinemia using the fixed TSH cut-offs [ 8 ] had to amend its protocols because the TSH upper limit turned out to be 4.0 mU/l after roughly 15.000 women were screened. The 2017 ATA guidelines [ 9 ] now recommend the following: Calculate pregnancy-specific and lab-specific references ranges for TSH and FT4 If 1 is not possible, adopt a reference range from the literature that is derived using a similar assay and preferably also in a population with similar characteristics (i.e. ethnicity, BMI, iodine status) If 1 and 2 are not possible, deduct 0.5 mU/l from the non-pregnancy reference range (which in most centers would results in a cut-off of roughly 4.0 mU/l) My interpretation of these recommendations is probably more strict than that of most endocrinologists or gynecologists. Lab-specific reference ranges better identify women with gestational thyroid dysfunction than reference ranges defined by another methodology [ 7 , 10 ]. Calculating lab-specific references ranges is not difficult and every hospital in which prenatal care is provided would be able to perform a good study at very low costs (i.e. less than a few thousand euro/GBP), particularly when collaborating with the clinical chemistry department. Adequate reference ranges can be obtained by selecting at least 400 pregnant women with a singleton pregnancy, free of pre-existing thyroid disease, that do not use thyroid interfering medication, that did not undergo IVF treatment and are TPOAb negative [ 7 ]. Therefore, I believe that if a center does not have lab-specific reference ranges readily available, physicians should not automatically move to step 2 or 3 of the guideline recommendations, but try to obtain lab-specific reference ranges. Calculating such reference ranges will instantly improve the quality of clinically diagnosing thyroid dysfunction in pregnancy. When specific expertise is missing, groups involved in the field of thyroid and pregnancy (including our group) would be more than willing to share their experience. Although it seems clear that fixed upper TSH limits of 2.5 mU/l or 3.0 mU/l can no longer be considered adequate, the new ATA guidelines seem to make one exception. A new recommendation indicates that levothyroxine treatment can be considered for a TSH above the reference range in TPOAb negative women, while for TPOAb positive women treatment can be considered from a TSH above 2.5 mU/L [ 9 ]. This is based on data from observational studies showing that there is a higher risk of miscarriage and premature delivery in TPOAb positive women with high-normal TSH concentrations (i.e. above roughly 2.5 mU/L). However, new studies published only shortly after release of the new guidelines could not show any beneficial effect of levothyroxine treatment for women with a TSH above 2.5 mU/L, but did find beneficial effects for women with a TSH above 4.0 mU/L [ 11 , 12 , 13 ]. However, larger studies are needed to confirm these findings and identify the true TSH concentration from which the outcome of clinical adverse outcomes is increased. While much focus has gone into defining the upper limit for TSH, the definition of thyroid dysfunction is also dependent on the FT4 concentration. For example, in a hypothetical patient with a TSH of 5.5 mU/l, the FT4 concentration will decide whether there is overt hypothyroidism or subclinical hypothyroidism. The distinction between these clinical disease entities can have major consequences for the clinical work-up and approach. Although some studies have casted doubt about the validity of FT4 immunoassays during pregnancy, it is important to realize that the vast majority of patients present during early pregnancy during which the assay interference by thyroid hormone binding proteins is not relevant (only relevant during the third trimester). Moreover, lab-specific reference ranges for FT4 will still correctly identify women with true low or true high FT4 given that there is a high correlation between FT4 concentrations measured by immunoassays and after disequilibrium dialysis or with LCMS [ 1 ]. The alternative of increasing the non-pregnancy limits for total T4 by 150% does not seem viable given the gestational age specific changes and lack of association of total T4 with adverse outcomes [ 1 , 14 ]. Conclusions In conclusion, any hospital or physician that is still using the 2.5 or 3.0 mU/l cut-off for TSH during pregnancy should re-evaluate their practice. 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Written by Theodore T Zava  & David T Zava   Thyroid Research volume 4 , Article number: 14 (2011) Abstract Japanese iodine intake from edible seaweeds is amongst the highest in the world. Predicting the type and amount of seaweed the Japanese consume is difficult due to day-to-day meal variation and dietary differences between generations and regions. In addition, iodine content varies considerably between seaweed species, with cooking and/or processing having an influence on iodine content. Due to all these factors, researchers frequently overestimate, or underestimate, Japanese iodine intake from seaweeds, which results in misleading and potentially dangerous diet and supplementation recommendations for people aiming to achieve the same health benefits seen by the Japanese. By combining information from dietary records, food surveys, urine iodine analysis (both spot and 24-hour samples) and seaweed iodine content, we estimate that the Japanese iodine intake--largely from seaweeds--averages 1,000-3,000 μg/day (1-3 mg/day). Introduction Japanese iodine intake exceeds that of most other countries, primarily due to substantial seaweed consumption. Iodine is an essential element required for thyroid hormone synthesis, believed to impart some of its antioxidant and antiproliferative activity in the prevention of cardiovascular disease and cancer [ 1 – 8 ]. Seaweeds have the unique ability to concentrate iodine from the ocean, with certain types of brown seaweed accumulating over 30,000 times the iodine concentration of seawater [ 9 ]. The amount of iodine the Japanese consume daily from seaweeds has previously been estimated as high as 13.5 to 45 mg/day by sources that use ambiguous data to approximate intake [ 10 , 11 ], an amount 4.5 to 15 times greater than the safe upper limit of 3 mg/day set by the Ministry of Health, Labor and Welfare in Japan [ 12 ]. While high iodine intake from seaweed consumption is believed to have numerous health benefits, it has been reported to negatively affect individuals with underlying thyroid disorders [ 13 – 16 ]. To prevent excessive consumption it is imperative for people seeking health benefits from a high iodine diet to be knowledgeable of the amount of iodine the Japanese consume daily. In this paper we use a combination of dietary records, food surveys, urine iodine analysis, and seaweed iodine content to provide a reliable estimate of Japanese iodine intake, primarily from seaweeds. Types of edible seaweeds and their iodine content In Japan, over 20 species of red, green, and brown algae (seaweed) are included in meals [ 17 ]. Iodine content varies depending on species, harvest location and preparation, and is typically highest in fresh cut blades and lowest in sun bleached blades [ 18 ]. The three most popular seaweed products in Japan are nori ( Porphyra ), wakame ( Undaria ) and kombu ( Laminaria ). Dried iodine contents range from 16 μg/g in nori to over 8,000 μg/g in kelp flakes; Japanese kombu and wakame contain an estimated 2353 μg/g and 42 μg/g respectively [ 18 , 19 ]. Ten different species of Laminaria , a type of kelp commonly labeled as kombu, from around the world were examined for their iodine content and were found to average 1,542 μg/g when dried [ 17 ]. Japanese seaweed consumption statistics As the Japanese transitioned from a traditional to a Westernized diet, beginning around the 1950's [ 20 ], consumption of certain seaweed species declined while others increased. A decrease in kombu consumption (844 to 685 g/year per household) and an increase in wakame consumption (727 to 1234 g/year per household) can be seen between the years of 1963 and 1973 [ 21 ]. Consumption of kombu per Japanese household dropped further to 450 g in 2006 (elders ate up to four times more than those under the age of 29) [ 19 ]. Since daily seaweed consumption per person in Japan has remained relatively consistent over the last 40 years (4.3 g/day in 1955 and 5.3 g/day in 1995) [ 22 ], it is believed that consumption of wakame and nori have made up for the decline in kombu consumption [ 23 , 24 ]. Both nori and wakame have relatively low iodine contents compared to kombu. Seaweed consumption frequency differs from person to person in Japan, resulting in a constantly fluctuating iodine intake. Seaweed is served in approximately 21% of Japanese meals [ 25 ] with 20-38% of the Japanese male and female population aged 40-79 years consuming seaweed more than five times per week, 29-35% three to four times per week, 25-35% one to two times per week, 6-13% one to two times per month, and 1-2% rarely consuming seaweed [ 26 ]. A 2010 food frequency questionnaire on the Japanese Kombu Association website indicates that kelp (assuming kombu) is consumed at a rate of: 27.5% once per week, 25.5% once per month, 18% three or four times per week, and 15.9% once every few months, with only 6.1% of survey respondents stating they consume kelp nearly every day [ 27 ]. Effect of cooking on seaweed iodine content Seaweed is often cooked to flavor dishes or soup stocks before consumption. When kombu is boiled in water for 15 minutes it can lose up to 99% of its iodine content, while iodine in sargassum, a similar brown seaweed, loses around 40% [ 28 , 29 ]. Processed kelp is often boiled in dye for half an hour ("ao-kombu" or "kizami-kombu") before hanging to dry [ 21 ], a process which can reduce seaweed iodine content before it is consumed. When kelp is used to flavor soup stocks the seaweed is often removed after boiling, resulting in soup stock high in iodine. Twenty samples of supermarket soups with kelp or kelp broth were analyzed by Nishiyama et al. to determine iodine content, revealing a minimum concentration of 660 μg/L (0.66 mg/L) and a maximum concentration of 31,000 μg/L (31 mg/L) [ 16 ]. Serving size for soup is typically around 0.25 L, resulting in 165 to 7,750 μg (0.165 to 7.75 mg) of iodine per serving. Estimating Japanese iodine intake from seaweed consumption Due to variation of iodine content from one seaweed species to the next, along with confusion stemming from wet and dry weight terminology, many inaccurate assumptions have been made regarding the amount of iodine the Japanese actually consume from seaweed. Not all studies, dietary records or surveys specify whether daily or yearly consumption of seaweeds is recorded using wet weight, dry weight or a combination of the two. In some reports seaweed consumption has been estimated at 4-7 g/day dried weight [ 17 , 22 , 30 , 31 ], while other reports claim consumption of 12 g/day using both wet and dry weight  [ 32 ]. Certain seaweeds have a swelling capacity of nearly ten times their dry volume with moisture content typically over 70% when wet and around 7-20% when dried [ 33 , 34 ]. The difference between wet and dry weight, along with the type of seaweeds being consumed, can result in extreme overestimation (more likely) or underestimation (less likely) of Japanese iodine intake. Interpreting information to determine Japanese seaweed consumption and resulting iodine intake is a difficult task, and with ever changing diets, a close estimate is all that can be made. Nori and wakame are the most commonly consumed seaweeds in Japan, with nori accounting for 45% and wakame accounting for 30% (75% together) of total seaweed consumption, as stated by the Food and Agriculture Organization of the United Nations [ 35 ]. Based on previous estimates and records, dried seaweed consumption of 4-7 g/day [ 17 , 22 , 30 , 31 ] results in iodine intakes between 79 and 139 μg/day from nori and wakame when calculated using dried iodine contents of 16 and 42 μg/g respectively [ 18 ]. The remainder of iodine intake is derived mainly from kombu consumption, with smaller amounts coming from other seaweeds that have nominal iodine content. Kombu has the highest iodine content of all seaweeds in the Japanese diet. In 2006 consumption of kombu/household/year was 450 g [ 19 ], and with an average of 2.55 members per household in Japan in 2005 [ 36 ], 0.48 g kombu/person/day was consumed. When calculated, 0.48 g of kombu with an iodine content of 2,353 μg/g [ 18 ] equates to 1,129 μg/day of iodine. Assuming negligible iodine intake from the other seaweeds consumed, daily iodine intake from nori, wakame, and kelp can be estimated at 1,208 to 1,268 μg/day (1.2 to 1.3 mg/day). It is reasonable to assume that iodine intake per day based on seaweed consumption frequency and iodine content averages around 1,000-2,000 μg/day (1-2 mg/day). Estimating Japanese iodine intake from diet studies and urine iodine analysis Seaweed consumption statistics only provide only an estimate of Japanese iodine intake and should be combined with other predictive factors. Fortunately, studies that measure iodine content of single or entire meals are available and are, arguably, the most accurate estimate of Japanese iodine intake from seaweeds. A collection of Japanese diet studies that measure the amount of iodine in 24-hour diet samples or single meals can be seen in Table 1 . Daily iodine intake of the Japanese based on 24-hour diet samples generally does not exceed 3,000 μg (3 mg). Because approximately 97% of dietary iodine is excreted in the urine, urine iodine levels taken from individuals or populations can provide a secondary estimate of Japanese iodine intake from seaweed consumption, when paired with diet studies [ 37 , 38 ]. Urine iodine levels can increase from 100 μg/L to 30,000 μg/L in a single day and return to 100 μg/L within a couple of days, depending on seaweed intake [ 39 ]. This is somewhat expected when varying amounts and types of seaweeds are consumed on a day-to-day basis. Urine creatinine levels seen as μg iodine/g creatinine ( μg/g Cr) can be used to adjust for an individual's hydration status, correlating well with μg/L in areas of adequate nutrition [ 40 ]. Urine iodine levels of the Japanese found in a number of studies are shown in Table 2 . Mean and median iodine levels in the Japanese urine collections typically do not exceed 3,000 μg/L (3 mg/L). When using 1.5 L as an expected 24-hour urine output, urine iodine excretion should rarely exceed an estimated 4,500 μg/24 hr (4.5 mg/24 hr). Japanese health statistics linked to high seaweed intake The Japanese are considered one of the world's longest living people, with an extraordinarily low rate of certain types of cancer. A major dietary difference that sets Japan apart from other countries is high iodine intake, with seaweeds the most common source. Here are some astonishing Japanese health statistics, which are possibly related to their high seaweed consumption and iodine intake: Japanese average life expectancy (83 years) is five years longer than US average life expectancy (78 years) [ 41 ]. In 1999 the age-adjusted breast cancer mortality rate was three times higher in the US than in Japan [ 42 ]. Ten years after arriving in the US (in 1991), the breast cancer incidence rate of immigrants from Japan increased from 20 per 100,000 to 30 per 100,000 [ 43 ]. In 2002 the age-adjusted rate of prostate cancer in Japan was 12.6 per 100,000, while the US rate was almost ten times as high [ 44 ]. Heart related deaths in men and women aged 35-74 years are much higher in the US (1,415 per 100,000) as they are in Japan (897 per 100,000) [ 45 ]. In 2004, infant deaths were over twice as high in the US (6.8 per 1,000) as they were in Japan (2.8 per 1,000) [ 46 ]. Negative effects of iodine from seaweed High iodine intake from seaweed consumption can cause unexpected health problems in a subset of individuals with pre-existing thyroid disorders. Although it is reported that excessive iodine does not cause thyroid antibody positivity, high intake can cause or worsen symptoms for people with previous thyroid autoimmunity or other underlying thyroid issues [ 47 ]. Transient hypothyroidism and iodine-induced goiter is common in Japan and can be reversed in most cases by restricting seaweed intake [ 16 , 29 , 48 – 52 ]. In Asian cultures, seaweed is commonly cooked with foods containing goitrogens such as broccoli, cabbage, bok choi and soy [ 18 ]. The phytochemicals in these foods can competitively inhibit iodine uptake by the thyroid gland (i.e., isothiocyanates from cruciferous vegetables) [ 53 – 55 ], or inhibit incorporation of iodine into thyroid hormone (i.e., soy isoflavones) [ 56 , 57 ]. Certain species of seaweed can concentrate bromine, a halide similar to iodine with no known physiological function, at very high levels [ 58 , 59 ]. If seaweeds with elevated levels of bromine and low levels of iodine are consumed when the body is in an iodine deficient state, inhibition of thyroid hormone synthesis--due to bromine's attachment to tyrosine residues on thyroglobulin in place of iodine--is plausible [ 60 ]. Estimate of daily iodine intake in Japan We estimate that the average Japanese iodine intake, largely from seaweed consumption--based on dietary records, food surveys, urine iodine analysis and seaweed iodine content--is 1,000-3,000 μg/day (1-3 mg/day). This estimate compares to a recent report claiming that the average iodine intake of the Japanese from kelp is around 1,200 μg/day (1.2 mg/day) [ 19 ]. Iodine intake can vary from day-to-day depending on diet, and it is unlikely for a single persons iodine intake to remain constant for an extended period of time. With the multitude of edible seaweeds (each with different iodine content) consumed in the Japanese diet, it is not appropriate to use a single type of seaweed to determine iodine intake, though many estimates do. Although seaweed provides a majority of the Japanese iodine intake, other food sources (containing far less iodine)--such as fish and shellfish--can increase the total amount of iodine consumed daily. Conclusions Japanese iodine intake from seaweed is linked to health benefits not seen in cultures with dissimilar diets. 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Written by Adam Gesing , Andrzej Lewiński  & Małgorzata Karbownik-Lewińska   Thyroid Research volume 5 , Article number: 16 (2012)                                                                                     Abstract The endocrine system and particular endocrine organs, including the thyroid, undergo important functional changes during aging. The prevalence of thyroid disorders increases with age and numerous morphological and physiological changes of the thyroid gland during the process of aging are well-known. It is to be stressed that the clinical course of thyroid diseases in the elderly differs essentially from that observed in younger individuals, because symptoms are more subtle and are often attributed to normal aging. Subclinical hypo- and hyperthyroidism, as well as thyroid neoplasms, require special attention in elderly subjects. Intriguingly, decreased thyroid function, as well as thyrotropin (TSH) levels – progressively shifting to higher values with age – may contribute to the increased lifespan. This short review focuses on recent findings concerning the alterations in thyroid function during aging, including these which may potentially lead to extended longevity, both in humans and animals. Introduction The endocrine system and particular endocrine organs, including the thyroid gland, undergo – similarly to other organ systems – crucial functional changes with aging. Numerous morphological and physiological changes of the thyroid during the process of aging are well-known [ 1 – 3 ]. A specificity of thyroid diseases in the elderly, differing essentially from that observed in younger subjects, relies on the presence of more subtle symptoms which are often attributed to normal aging. Therefore, subclinical hypo- and hyperthyroidism, as well as thyroid neoplasms, the prevalence of which increases with age, require special attention in elderly subjects. Interestingly, altered thyroid function may contribute to the extended longevity. The present review focuses on the newest findings concerning the alterations in thyroid function during the process of aging. Thyroid dysfunction with aging The process of aging affects both the prevalence and clinical presentation of hypo- and hyperthyroidism. Importantly, subclinical disturbances of thyroid function are more frequent than overt diseases in general population, as well as in elderly people [ 4 , 5 ]. Consistently, the prevalence of subclinical hypothyroidism, which is characterized by normal free thyroxine (FT4) and elevated thyrotropin (TSH) levels, increases with aging [ 6 – 12 ] and ranges from 3 to 16% in individuals aged 60 years and older [ 13 ]. Although it is known that overt thyroid disorders negatively affect physical and cognitive function in elderly people – for example, overt hypothyroidism is associated with the impairment of attention, concentration, memory, perceptual functions, language, and executive functions [ 14 ], subclinical hypothyroidism is not associated with impairment of physical and cognitive function or depression in individuals aged 65 years and older, as compared to euthyroidism [ 15 ]. Also Park et al. [ 16 ] have demonstrated that subclinical hypothyroidism in elderly subjects is neither associated with cognitive impairment, depression, poor quality of life nor with metabolic disturbances. On the other hand, other studies demonstrated the presence of – at least – mild cognitive impairment in people with subclinical hypothyroidism at mean age under 65 years (reviewed in [ 17 ]). Furthermore, as reported by de Jongh et al. [ 15 ], subclinical hypothyroidism was also not associated with the increased overall mortality risk. Similar findings were shown by Rodondi et al. [ 18 ] who analyzed data from numerous large prospective cohorts and demonstrated that total mortality was not increased in subjects with subclinical hypothyroidism, although the risk of coronary heart disease (CHD) events and of CHD mortality increased with TSH levels 10 mIU/l or higher. Nevertheless, it should be emphasized that this analysis regarded numerous different populations (cohorts) which consisted of not only elderly people and that the effect in question, i.e. of increasing TSH level on CHD incidents was not influenced by age [ 18 ]. Undoubtedly, there are obvious indications for treatment of overt hypothyroidism. On the other hand, indications for treatment of subclinical hypothyroidism are still controversial. Despite improvement of lipid profile due to treatment of subclinical hypothyroidism, there is no clear evidence that this beneficial effect can be associated with decreased cardiovascular or all-cause mortality in elderly patients [ 19 ]. Furthermore, Parle et al. [ 20 ] have reported that L-thyroxine replacement therapy does not improve cognitive function in elderly individuals with subclinical hypothyroidism. When the natural history of subclinical hypothyroidism was evaluated in the elderly, the final results depended on the presence or absence of thyroid antibodies and on that to what extent TSH concentration was increased. Thus, a quite high rate of reversion of subclinical hypothyroidism to euthyroid status in adults aged at least 65 years with lower baseline TSH levels and antithyroid peroxidase antibody (TPOAb) negativity was observed [ 21 ]. In turn, higher TSH level and TPOAb positivity were independently associated with lower chance of reversion to euthyroidism [ 21 ]. Moreover, TSH levels ≥ 10 mIU/l were independently associated with progression to overt hypothyroidism [ 21 ]. Similar findings, showing that higher baseline TSH levels are associated with progression from subclinical to overt hypothyroidism and that higher TSH level (> 8 mIU/l) is a predictive value for development of overt hypothyroidism, were recently reported by Imaizumi et al. [ 22 ]. On the other hand, there is strong evidence that thyroid hypofunction may contribute to increased lifespan (see further in the text). Therefore, taking into account all mentioned observations, the replacement therapy with L-thyroxine is not uniformly recommended in elderly people with subclinical hypothyroidism. In turn, subclinical hyperthyroidism, characterized by serum TSH levels below lower limit of the reference range and normal serum FT4 levels, is observed in about 8% of individuals aged 65 years and older [ 23 ]. Subclinical hyperthyroidism may be associated in older adults with decreased bone mineral density and fractures [ 24 ], or cognitive impairment [ 23 ] (reviewed in [ 25 ]). Furthermore, subclinical hyperthyroidism is associated with increased risk of total, as well as CHD mortality and atrial fibrillation (AF) incidents [ 26 ]. The highest risks of CHD mortality and AF are observed in the case of TSH levels lower than 0.1 mIU/l [ 26 ]. Unexpectedly, de Jongh et al. [ 15 ] have reported that subclinical hyperthyroidism is not associated with impairment of physical and cognitive function or depression in elderly people, aged 65 years and older. These authors have also demonstrated that subclinical hyperthyroidism is not associated with the increased overall mortality risk [ 15 ]. Such results are quite difficult to explain. Presumably, that ambiguity in observations may result from differences in the number of individuals enrolled in particular studies or from follow-up duration. Interestingly, Rosario [ 27 ] has recently shown that progression of subclinical hyperthyroidism to overt hyperthyroidism in elderly patients is an uncommon observation. Nevertheless, since subclinical hyperthyroidism (and obviously, overt hyperthyroidism with increased T4 level) may lead to increased risk of total, as well as CHD mortality, patients older than 65 years, with low TSH levels – particularly in case of toxic multinodular goitre or a solitary autonomous thyroid nodule – require proper medical treatment (e.g. [ 11 ]). It should also be stressed that during aging, gender-specific alterations in TSH and free thyroid hormone levels were observed [ 28 ]. Namely, with increasing age in males there were decreases in free thyroid hormones but not in TSH concentrations. In turn, in females, the free thyroid hormone levels were not changed with aging but TSH level increased in age-dependent manner [ 28 ]. Most recent results indicate that even in euthyroid older men with normal levels of TSH, differences in FT4 levels within the normal range predict specific health outcomes relevant to aging. For example, higher FT4 within the normal range was independently associated with frailty in euthyroid men aged ≥70 years [ 12 ]. Moreover, higher FT4 levels within the normal range were associated with lower hip bone mineral density, increasing bone loss and fracture risk in postmenopausal women [ 29 ]. Therefore, it seems that further studies are required to explain whether higher FT4 levels contribute causally (or not) to the above mentioned poorer health outcomes. Moreover, it is of interest to clarify whether FT4 levels in the low-normal range could be considered as potential biomarkers for healthy aging [ 12 ]. Although numerous studies demonstrate that the increased TSH level resulting from subclinical hypothyroidism further rises with aging [ 6 – 12 ], other findings suggest that aging is associated – in the absence of any thyroid disease – with lower TSH levels [ 30 – 35 ]. It has been known that TSH secretion in response to thyrotropin-releasing hormone (TRH) is reduced in aging individuals, and serum TSH level is usually lower in older than in young people in response to decreased thyroid hormone concentrations, suggesting a certain level of insensitivity of thyrotrophic cells in anterior pituitary, occurring with age; moreover, nocturnal surge of TSH is – to various degree – lost in the elderly (reviewed in [ 1 ]). On the other hand, Bremner et al. [ 10 ] have recently reported that the TSH increase – observed by other authors during aging – seems to be a consequence of age-related alteration in the TSH set point or reduced TSH bioactivity. Interestingly, the largest TSH increase is observed in people with the lowest TSH at baseline, and, in turn, people with higher baseline TSH levels had proportionally smaller increases in TSH concentrations [ 10 ]. It is worth adding that TRH and FT4 serum levels do not differ between young, middle-aged and elderly subjects [ 34 ]. Thyroid dysfunction and longevity As it has been mentioned above, the alterations in levels of hormones related to pituitary-thyroid axis are associated with the process of aging and, thus, may impact longevity. However, a direction of these changes, which may lead to increased lifespan, still seems to be not fully determined [ 6 – 12 , 30 – 35 ]. One should emphasize that the most striking findings concerning potential contribution of TSH and thyroid hormones to lifespan regulation, were obtained in the studies performed on centenarians (and almost centenarians). In 2009, Atzmon et al. [ 7 ] published the results of studies on thyroid disease-free population of Ashkenazi Jews, characterized by exceptional longevity (centenarians). They have observed higher serum TSH level in these subjects as compared to the control group consisted of younger unrelated Ashkenazi Jews, as well as to another control group obtained from The National Health and Nutrition Examination Survey (NHANES) program of studies [ 7 ]. Therefore, these findings appear to support previous observations, indicating that serum TSH shifts progressively to higher levels with age (e.g., [ 36 ]). Moreover, the authors have observed an inverse correlation between FT4 and TSH levels in centenarians and Ashkenazi controls, and finally, they have distinctly concluded that increased serum TSH is associated with extreme longevity [ 7 ]. In another study, a role of genetic background, potentially responsible for the above-mentioned changes, was assessed [ 37 ]. It turned out that two (2) single nucleotide polymorphisms (SNPs) in TSH receptor (TSHR) gene, namely rs10149689 and rs12050077, were associated with increased TSH level in the Ashkenazi Jewish centenarians and their offspring [ 37 ]. The above-mentioned inverse correlation between FT4 and TSH in centenarians may suggest a potential role of decreased thyroid function in lifespan regulation, leading to remarkable longevity. Such a hypothesis seems to have been confirmed by the findings obtained in the Leiden Longevity Study, demonstrating the associations between low thyroid activity and exceptional familial longevity [ 38 ]. In turn, Corsonello et al. [ 39 ] have demonstrated that age is associated with a decrease in free triiodothyronine (FT3) and FT4 but not with increased TSH levels. Moreover, children and nieces/nephews of centenarians had lower FT3, FT4 and TSH levels as compared to the age-matched subjects [ 39 ]. It may, at least partially, confirm an important role of low thyroid function in the regulation of lifespan. It should be stressed that reduced thyroid function with low levels of T4 is associated with extended longevity also in animals [ 40 – 42 ]. For example, a very severe thyroid hypofunction with reduced core body temperature, as observed in Ames dwarf (df/df) and Snell mice (characterized by mutations at the Prop-1 and Pit-1 gene, respectively, and demonstrating a lack of growth hormone (GH), prolactin and TSH), is considered to substantially contribute to remarkable longevity in these rodents [ 40 ]. Furthermore, severe hypothyroid Ames dwarfs and mice with targeted disruption of the growth hormone receptor/growth hormone binding protein gene (GH receptor knockout; GHRKO) with mild thyroid hypofunction, have decreased thyroid follicle size which may explain decreased thyroid hormone levels in these mutants [ 43 ]. Concluding, the findings in animals are consistent with the results obtained in humans and may confirm a relevant role of thyroid hypofunction in lifespan extension. Thyroid cancerogenesis and aging processes The prevalence of thyroid nodules and thyroid neoplasms is increased in the elderly. Among elderly people, males are at higher risk of cancer and thyroid cancer is more aggressive in men than in women [ 44 ]. Papillary thyroid carcinoma (PTC) is the most common endocrine malignant neoplasm in the older individuals. Women are affected by PTC two to three times more often than men [ 45 ]. Nevertheless, female-to-male ratio seems to decline with the process of aging [ 45 ]. Importantly, the mortality rate of PTC is usually higher in the elderly [ 46 ]. Presumably, it is a consequence of increased mitotic activity of these tumors and increased likelihood of distant metastases [ 46 ]. It is known that in general population patients with aggressive variants of PTC have higher risk for the metastatic disease development [ 47 ]. The potential role of NDRG2 gene expression in the development and progression of PTC is also raised [ 48 ]. It is worth recalling that mutated BRAF gene is an independent predicting factor of poor outcome in PTC and is related to advanced age [ 49 ]. Follicular thyroid carcinoma (FTC) occurs also often in older people and is the second most common and the second least aggressive thyroid cancer. This cancer is more likely to metastasize hematogenously to distant sites, resulting in a worse prognosis in comparison with PTC [ 44 ]. Medullary thyroid carcinoma (MTC), which derives from the parafollicular cells (C cells) of the thyroid gland, constitutes up to 5% of all thyroid malignancies. Its sporadic form, more frequent than is familial MTC, occurs more commonly in the older population [ 50 ]. Rapidly growing and typically very aggressive anaplastic (undifferentiated) thyroid carcinoma (ATC) is rare. However, one should strongly emphasize that its prevalence is considerably higher in older than in younger people. By the time of diagnosis, most patients have widespread local invasion and distant metastases. Age appears to be a strong predictor of poor prognosis in ATC [ 44 ]. Conclusions The process of aging strongly affects entire endocrine system. Consistently, thyroid gland is also impacted by aging. One should emphasize that thyroid diseases-associated symptoms in the elderly people are very similar to symptoms of the normal aging. Therefore, broadening the knowledge on alterations in thyroid function, which may be observed during aging, appears to be very important and constitutes a challenge for thyroid researchers, given that some specific thyroid dysfunctions may contribute to lifespan extension. 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Written by Agata Bielecka-Dabrowa , Dimitri P Mikhailidis , Jacek Rysz  & Maciej Banach   Thyroid Research volume 2 , Article number: 4 (2009) Abstract Atrial fibrillation (AF) is a complex condition with several possible contributing factors. The rapid and irregular heartbeat produced by AF increases the risk of blood clot formation inside the heart. These clots may eventually become dislodged, causing embolism, stroke and other disorders. AF occurs in up to 15% of patients with hyperthyroidism compared to 4% of people in the general population and is more common in men and in patients with triiodothyronine (T3) toxicosis. The incidence of AF increases with advancing age. Also, subclinical hyperthyroidism is a risk factor associated with a 3-fold increase in development of AF. Thyrotoxicosis exerts marked influences on electrical impulse generation (chronotropic effect) and conduction (dromotropic effect). Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk, including elevation of left atrial pressure secondary to increased left ventricular mass and impaired ventricular relaxation, ischemia resulting from increased resting heart rate, and increased atrial eopic activity. Reentry has been postulated as one of the main mechanisms leading to AF. AF is more likely if effective refractory periods are short and conduction is slow. Hyperthyroidism is associated with shortening of action potential duration which may also contribute to AF. Introduction Atrial fibrillation (AF) is a common dysrrhythmia representing an independent risk factor for cardiovascular events [ 1 ]. The rapid and irregular heartbeat produced by AF increases the risk of blood clot formation inside the heart. These clots may eventually become dislodged, causing embolism, stroke and other disorders [ 1 , 2 ]. AF is a complex disease with several possible mechanisms. Studies indicate that arrhythmogenic foci within the thoracic veins can be AF initiators [ 2 ]. Once initiated, AF alters atrial electrical and structural properties in a way that promotes its own maintenance; this increases the risk of recurrence and may alter the response to antiarrhythmic drugs [ 2 , 3 ]. AF may occur in patients with a variety of cardiovascular or chronic diseases as well as in normal subjects. It is the most common cardiac complication of hyperthyroidism [ 3 ]. AF in thyrotoxicosis is associated with significant mortality and morbidity resulting from embolic events [ 3 ]. The risk factors for AF in patients with hyperthyroidism (age, male sex, ischemic heart disease, congestive heart failure and valvular heart disease) are similar to those in the general population [ 4 ]. AF occurs in up to 15% of patients with hyperthyroidism [ 5 ] compared with 4% incidence in the general population [ 6 ] and is more common in men and in patients with triiodothyronine (T3) toxicosis [ 3 ]. Also, subclinical hyperthyroidism is a risk factor that is associated with a 3-fold increase in risk of developing AF [ 5 ]. AF incidence increases with advancing age. Although it is rare in patients under 40 years of age, 25% to 40% of hyperthyroid individuals over the age of 60 experience AF, possibly reflecting an age-related reduction in threshold for acquiring this arrhythmia. Of hyperthyroid patients older than 60 years, 25% had AF compared with 5% prevalence in patients younger than 60 years [ 7 ]. Patients with toxic nodular goiter also showed, because of their age, an increased prevalence of AF versus younger patients with Graves' disease (43% vs 10%, respectively). Also, analysis of rhythm disorders in 219 patients with hyperthyroidism [ 8 ] showed an age-dependent distribution of AF and sinus node dysfunctions. In a large study [ 9 ] of patients with new-onset AF, less than 1% of AF incidence was caused by overt hyperthyroidism. Therefore, although serum thyroid-stimulating hormone (TSH) is measured in all patients with new-onset AF to rule out thyroid disease, this association is uncommon in the absence of additional symptoms and signs of hyperthyroidism. Treatment of hyperthyroidism results in conversion to sinus rhythm in up to two-thirds of patients. In a prospective trial, the arrhythmia profile was analyzed in hyperthyroid patients, before, during, and after antithyroid therapy [ 10 ]. The number of patients with atrial premature complexes was elevated compared with controls (88 vs 30%) and decreased markedly after treatment. As with other causes of AF, the main determinant of reversion seems to be the duration of AF [ 11 ]. Patients who had been in AF for more than 1 year and those who were in advanced age were likely to need intervention in the long run, probably reflecting the coexistence of ischaemic heart disease in these hyperthyroid patients with AF [ 12 ]. No association of subclinical hypothyroidism with AF has been found [ 5 , 13 – 15 ]. The 'hypothalamic -pituitary -thyroid axis' Thyroxine (T4) and triiodothyronine (T3) are tyrosine-based hormones produced by the thyroid gland. The major form of thyroid hormone in the blood is thyroxine (T4). The ratio of T4 to T3 in the blood is roughly 20 to 1. Thyroxine is converted to the active T3 form (3 to 4 times more potent than T4) by deiodinases. TSH stimulates the thyroid gland to secrete the thyroid hormones. TSH production is controlled by thyrotropin releasing hormone (TRH), which is synthesised in the hypothalamus and transported to the anterior pituitary gland via the superior hypophyseal artery, where it increases TSH production and release. Somatostatin is also produced by the hypothalamus, and has an opposite effect on the pituitary production of TSH, decreasing or inhibiting its release. The levels of T3 and T4 in the blood have a feedback effect on the pituitary release of TSH. When the levels of T3 and T4 are low, the production of TSH is increased, and conversely, when levels of T3 and T4 are high, then TSH production is decreased. This effect creates a regulatory negative feedback loop. Subclinical hyperthyroidism as a risk for AF Subclinical hyperthyroidism is defined as low serum thyrotropin concentration in an asymptomatic patient with normal serum T3 and T4 concentration [ 16 ]. The prevalence among adults is up to 12% and increases with age [ 16 – 18 ]. Subclinical hyperthyroidism can occur as a result of thyroid pathology such as Graves' disease, multinodular goiter, or autonomous toxic nodules or may be exogenous due to thyroxine therapy [ 18 ]. Subclinical hyperthyroidism may be a consequence of L-thyroxine (L-T4) therapy [ 19 ]. The abnormalities found in patients with subclinical hyperthyroidism are increased heart rate and prevalence of supraventricular arrhythmias and enhanced left ventricular mass (LVM) due to concentric remodeling [ 19 ]. The increase in LVM is associated with slightly enhanced systolic function and almost always with impaired diastolic function due to slowed myocardial relaxation [ 19 – 23 ]. It rarely corresponds to actual left ventricle hypertrophy and is related to the duration of subclinical hyperthyroidism rather than to circulating thyroid hormone levels. It is assumed that these changes develop in response to a chronic hemodynamic overload due to the mild hyperkinetic cardiovascular state [ 24 ]. It is reported that a low serum thyrotropin concentration in an asymptomatic person with normal serum thyroid hormone concentrations can be an independent risk factor for developing AF [ 24 , 25 ]. A retrospective cross-sectional study [ 14 ] compared AF prevalence in 1338 subjects with overt or subclinical hyperthyroidism due to autonomous thyroid nodules or Graves disease with AF prevalence in a control group of 22300 subjects admitted to a hospital. The prevalence of AF was 13.8% in patients with overt hyperthyroidism, 12.7% in those with subclinical hyperthyroidism, and 2.3% in euthyroid controls. The relative risk (RR) of AF in those with subclinical hyperthyroidism was 5.2 (95% CI, 2.1–8.7) compared with controls. Thus, a low serum TSH concentration is associated with a more than 5-fold higher likelihood for the presence of AF. There was no significant difference between the risk of AF in patients with subclinical and overt hyperthyroidism [ 14 ]. In another study [ 5 ] in patients older than 60 years, subjects with low thyrotropin (<0.1 mU/L) had a 28% incidence of AF compared with 11% in normal subjects. The patients with slightly lower serum thyrotropin concentration (0.1 to 0.4 mU/L) also had a higher risk of AF than those with a normal thyrotropin concentration (RR 1.6; p = 0.05). There was no significant difference in AF occurrence between overt and subclinical hyperthyroidism [ 5 ]. Similar findings have been reported by Cappola et al. [ 13 ] investigating incident AF in 3233 US community-dwelling subjects 65 years or older. After exclusion of those with preexisting AF, those with subclinical hyperthyroidism (1.6% of the cohort) had a greater incidence of AF compared with those with normal thyroid function over a period of 12 years [adjusted hazards ratio (HR), 1.98; 95% CI, 1.29–3.03]. In the study of Kwon et al. [ 25 ] the significance of serum TSH in the euthyroid patient with AF whose serum level of T3, T4, free T4 (fT4), and were absolutely within normal range was assessed. The cutoff serum TSH value that distinguished between paroxysmal and chronic AF was 1.568 U/mL (76% predictive power). There was a significantly lower serum TSH in paroxysmal AF in all age groups (p < 0.05). The authors suggest that serum TSH below the serum concentration of 1.5 U/mL can be a risk factor for developing AF. Overt hyperthyroidism and AF risk In a large study including more than 23000 persons, AF was present in 513 subjects (2.3%) in the group with normal values for serum TSH, and in 78 (12.7%) and 100 (13.8%) in the groups with subclinical and overt hyperthyroidism, respectively [ 14 ]. In the study of Gammage et al. [ 26 ], serum fT4 was an independent predictor of the presence of AF in the cohort as a whole, and this association was sustained after exclusion of those with overt thyroid dysfunction. Furthermore, when the analysis was further restricted to those classified as euthyroid (with normal serum TSH concentration), the relationship between serum fT4 and AF was still evident. In the Rotterdam Study [ 27 ] patients with high normal serum fT4 concentrations also had a higher risk of AF. The multivariate adjusted level of fT4 showed a graded association with the risk of AF (HR, 1.62; 95% CI, 0.84–3.14, highest versus lowest quartile; p for trend, 0.06). Effects of thyroid hormones on the cardiovascular system Overt hyperthyroidism induces a hyperdynamic cardiovascular state (high cardiac output with low systemic vascular resistance), which is associated with a faster heart rate, enhanced left ventricular systolic and diastolic function, and increased prevalence of supraventricular tachyarrhythmias [ 28 ]. Thyroid hormones may exert both genomic and nongenomic effects on cardiac myocytes [ 28 ]. The genomic effects of thyroid hormones are mediated by transcriptional activation or repression of specific target genes that encode both structural and functional proteins [ 29 ]. Triiodothyronine (T3) is the biologically active thyroid hormone that gets into the cardiomyocyte through specific transport proteins located within the cell membrane, and which then interacts with specific transcriptional activators (nuclear receptor α-1) or repressors (nuclear receptor α-2) [ 30 ]. Occupancy of these receptors by T3, in combination with recruited cofactors, allows the thyroid hormone-receptor complex to bind (nuclear receptor α-1) or release (nuclear receptor α-2) specific sequences of DNA (thyroid-responsive elements) that, in turn, by acting as cis - or trans -regulators, modify the rate of transcription of specific target genes [ 28 , 31 ]. Severely hyperthyroid patients can show signs of congestive heart failure in the absence of prior cardiac pathology [ 32 ]. Cardiac manifestations in hyperthyroid patients can be the result of thyrotoxicosis itself, underlying heart disease that decompensates due to hyperthyroidism-induced increased demand on the heart, or increased occurrence of specific cardiac abnormalities [ 32 ]. Hyperthyroid patients frequently complain of dyspnea on exertion even in the absence of cardiac failure [ 33 ]. Because hyperthyroidism leads to a weakening of skeletal and intercostal muscles, dyspnea may be related more to a weakness of respiratory muscles than to cardiac abnormalities themselves [ 33 – 38 ]. Several lines of evidence suggest that some abnormalities of cardiac function in patients with thyroid dysfunction directly reflect the effects of thyroid hormones on calcium-activated ATPase and phospholamban, which are involved primarily in the regulation of systodiastolic calcium concentrations in cardiomyocytes [ 34 ]. Sarcoplasmic reticulum calcium-activated ATPase is responsible for the rate of calcium reuptake into the lumen of the sarcoplasmic reticulum during diastole that, in turn, is a major determinant of the velocity of myocardial relaxation after contraction [ 29 , 34 ]. It has been extensively demonstrated that thyroid hormone upregulates expression of the sarcoplasmic reticulum calcium-activated ATPase and downregulates expression of phospholamban, thereby enhancing myocardial relaxation [ 29 , 34 ]. The improved calcium reuptake during diastole may favorably affect myocardial contractility [ 34 ]. Some evidence indicates that thyroid hormones promote the acute phosphorylation of phospholamban and that this action attenuates the inhibitory effect of phospholamban on sarcoplasmic reticulum calcium-activated ATPase [ 35 ]. Interestingly, the fact that this process is mediated at least in part by the activation of intracellular kinase pathways involved in signal transduction of adrenaline [ 35 ] may help to explain functional analogies between the cardiovascular effects of thyroid hormone and those promoted by the adrenergic system [ 36 ]. The circadian rhythm of heart rate is maintained in thyrotoxicosis, although heart rate variability is significantly increased, supporting the view that normal adrenergic responsiveness persists in thyrotoxicosis [ 37 ]. Electrophysiological mechanism of AF in hyperthyroidism Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk, including elevation of left atrial pressure secondary to increased LVM and impaired ventricular relaxation [ 28 ], ischemia resulting from raised resting heart rate, and increased atrial ectopic activity [ 39 ]. Studies using an isolated heart model found that hearts from animals with experimental thyrotoxicosis show increased heart rates and shorter mean effective refractory periods than hearts from euthyroid animals [ 37 ]. In patients with hyperthyroidism increased heart rate and a decreased turbulence slope (TS) (TS quantifies the rate of sinus slowing that follows the sinus tachycardia) consistent with decreased vagal tone were observed [ 40 ]. Hyperthyroidism is associated with an increased supraventricular ectopic activity in patients with normal hearts [ 40 ]. Wustmann et al. [ 40 ] assessed the activity of abnormal supraventricular electrical depolarizations at baseline and follow-up after normalization of serum TSH levels. The abnormal premature supraventricular depolarization, the number of episodes of supraventricular tachycardia and nonsustained supraventricular tachycardia decreased significantly (p = 0.003, p < 0.0001, p = 0.01) after normalization of serum thyrotropin levels. The activation of arrhythmogenic foci by elevated thyroid hormones may be an important causal link between hyperthyroidism and AF. Heart rate effects are mediated by T3-based increases in systolic depolarization and diastolic repolarization and decrease in the action potential duration and the refraction period of the atrial myocardium, as well as the atrial/ventricular nodal refraction period. T3 induces electrophysiological changes partly due to its effects on sodium pump density and enhancement of Na+ and K+ permeability [ 41 ]. Expression of the L-type calcium channel 1D, which also serves as an important pacemaker function, is also increased by T3. In vitro studies found that T3 decreases the duration of the repolarization phase of the membrane action potential and increases the rate of the diastolic repolarization and therefore the rate of contraction [ 42 – 44 ]. Reentry has been postulated as one of the main mechanisms leading to AF [ 45 – 47 ]. Multicircuit wave fronts that are generated in the atrium could disturb normal sinus rhythm and set up a fibrillatory rhythm [ 45 – 47 ]. According to wavelength concepts, AF is more likely if effective refractory periods are short and conduction is slow [ 47 ]. Hyperthyroidism is associated with shortening of action potential duration [ 47 ]. Action potential duration (APD) determines the refractory period and is therefore a key determinant of the likelihood of reentry [ 46 , 47 ]. It has been reported that the properties of electrophysiological repolarization are not homogeneous within the 2 atria. Li et al. [ 48 ] determined that the higher density of the rapid delayed rectifier current ( I Kr) in left atrial myocytes contributed to the shorter effective refractory period and APD in canine left atrium. In several studies, changes have been observed in the expression of various ion channel mRNAs in both atria [ 49 , 50 ] and ventricles [ 49 , 51 , 52 ] under hyperthyroid conditions. Watanabe et al. [ 50 ] revealed a remarkable increase in the ultrarapid delayed rectifier potassium currents in hyperthyroid compared with euthyroid myocytes, whereas the transient outward potassium currents were unchanged. L-type calcium currents were decreased in hyperthyroid compared to euthyroid myocytes. T3 increased the outward currents and decreased the inward currents, resulting in shortened APD. Between the atrium and ventricle of the adult rat heart, the responses of gene expression of voltage-gated potassium channels to T3 were different and the variability of responses may explain cardiac manifestations of hyperthyroidism [ 49 ]. Hu et al. [ 53 ] assessed the electrophysiological changes that occur in left and right atria with hyperthyroidism, the patch-clamp technique was used to compare APD and whole cell currents in myocytes from left and right atria in both control and hyperthyroid mice. The RNAse protection assay and Western blotting were used to evaluate the mRNA and protein levels of α-subunits constituting the corresponding ion channel pore in the atrium. In hyperthyroid mice shortened APD and increased delayed rectifier currents (both the ultra-rapid delayed rectifier K+ conductance - I Kur and the sustained delayed rectifier K+ conductance - I ss) in atrial myocytes were observed. Messenger RNA and protein expression levels of the main potential pore-forming subunits for these 2 currents, Kv1.5 and Kv2.1, were also higher in both atria in this group. It is likely that increased Kv1.5 and Kv2.1 expression reflects increased channel synthesis and at least partially contributes to the higher density of I Kur and I ss obtained under hyperthyroid conditions. The association between alteration of Kv1.5 protein but not Kv2.1 expression and mRNA level was observed in hyperthyroid atria. This suggests that thyroid hormones may regulate Kv2.1 expression at a posttranscriptional level. The influence of hyperthyroidism on APD and delayed rectifier K+ currents was more prominent in right than in left atrium, which minimized the interatrial APD difference. Several factors such as differential pressure stress force, autonomic nerve innervation, or different transcriptional factor distribution between the 2 atria may play a role in this process. The overall shortening of action potential duration in hyperthyroid atria, which is reflective of a shorter effective refractory period, would facilitate the occurrence of reentry. Contrary to the normal interatrial APD difference that is important for synchronizing contraction of both atria (due to the physiological origination of sinus rhythm on the right side), the diminished interatrial APD difference may enhance the spreading of ectopic activity originating mostly from left atrium to the whole atria. Therefore, it is possible that the diminished interatrial APD would facilitate the generalization of irregular activities in a hyperthyroid state and provide the substrate for atrial arrhythmias such as AF [ 53 ]. Pulmonary veins are known to initiate paroxysmal AF [ 54 ]. Increased automaticity may also play a role in the arrhythmogenesis in hyperthyroid pulmonary veins [ 54 ]. Research using rabbit pulmonary vein cardiomyocytes has shown that thyroid hormones decrease the APD in pulmonary vein cardiomyocytes which can decrease the refractory interval and facilitate the genesis of reentrant circuits [ 54 , 55 ]. Incubation with thyroid hormones also increased spontaneous activity in pulmonary vein cardiomyocytes similar to its effect on sinoatrial node cells. Previous studies in humans or in isolated canine pulmonary vein tissues also have demonstrated that triggered activities may underlie the arrhythmogenic activity of pulmonary veins [ 55 , 56 ]. Thyroid hormones induced the occurrence of delayed after-depolarization (DAD) in beating and non-beating pulmonary vein cardiomyocytes. Transient inward currents have been suggested to play an important role in the genesis of DAD [ 57 , 58 ]. Tseng and Wit [ 57 ] showed that transient inward currents may play a role in the triggered activity of atrial cells in the coronary sinus. In the studies by Chen et al. [ 54 – 56 ] both the beating and non-beating hyperthyroid pulmonary vein cardiomyocytes had greater transient inward currents after being incubated with thyroid hormones, which may underlie the high incidence of DAD in these cells. In the beating cardiomyocytes, the incidence of early depolarization (EAD), defined as the generation of oscillatory potentials at depolarized levels, was also increased after incubation with thyroid hormones [ 54 – 56 ]. These findings suggest that thyroid hormones may induce the occurrence of paroxysmal AF through the increase of triggered activity in pulmonary veins. Thyroid hormones have little effects on the triggered activity of atrial cells, which suggests that these cells have different responses to thyroid hormone. Is it necessary to screen for thyroid function? Regarding the high incidence of AF in older patients with thyrotoxicosis, it is important to detect thyroid dysfunction in subjects over 60 year of age. Once euthyroidism is restored, all patients who revert spontaneously to sinus rhythm (~60%) do so within 4 months of becoming euthyroid [ 59 ]. The finding that subclinical hyperthyroidism detected as a result of screening is associated with AF contributes to the debate about the value of screening at-risk populations. This debate needs to be informed by evidence from trials investigating whether treatment prevents or reverses AF [ 26 ]. Screening thyroid function tests to exclude occult hyperthyroidism as the cause of AF should include total or free T3 and T4 and high sensitivity TSH measurements. Triiodothyronine concentration may be within the reference range in patients who are hyperthyroid and have AF [ 59 ]. The measurement of T4 alone can be also unsatisfactory, especially in patients with thyrotoxicosis, particularly if they have been treated for hyperthyroidism, with a nodular goitre or an autonomous thyroid nodule [ 60 ]. The TSH-producing cells of the anterior pituitary are sensitive to minor changes in circulating thyroid hormones and absent or subnormal TSH concentrations may be found in hyperthyroid patients in whom the T3 and T4 concentrations are higher than normal for the individual but within or at the upper end of the accepted reference range. An electrocardiogram may be helpful in identifying hyperthyroid subjects at risk for developing AF. Maximum P wave duration and P wave dispersion were higher in both subclinical and overt hyperthyroidism. P maximum and P wave dispersion were significant predictors of paroxysmal AF [ 60 – 62 ]. Conclusions Several potential mechanisms could be invoked for the effect of thyroid hormones on AF risk and this association is well documented in the literature. It is especially important to detect thyroid dysfunction in all subjects over 60 year of age, as once euthyroidism is restored all patients who revert spontaneously to sinus rhythm do so within 4 months of becoming euthyroid. The finding that subclinical hyperthyroidism detected as a result of screening is associated with AF contributes to the debate about the value of screening at-risk populations. This debate still needs to be informed by evidence from trials investigating whether treatment prevents or reverses AF [ 59 , 60 ]. 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OBS: Dette pakningsvedlegget finnes ikke på norsk. Her er orginialversjonen. ARMOUR THYROID- thyroid, porcine tablet Allergan, Inc. Disclaimer: This drug has not been found by FDA to be safe and effective, and this labeling has not been approved by FDA. ---------- Armour Thyroid (thyroid tablets, USP) Rx only DESCRIPTION Armour Thyroid (thyroid tablets, USP)* for oral use is a desiccated thyroid extract that is derived from porcine thyroid glands. (T3 liothyronine is approximately four times as potent as T4 levothyroxine on a microgram for microgram basis.) They provide 38 mcg levothyroxine (T4) and 9 mcg liothyronine (T3) per grain of thyroid. The inactive ingredients are calcium stearate, dextrose, microcrystalline cellulose, sodium starch glycolate and opadry white. Armour Thyroid may have a strong, characteristic odor due to its thyroid extract component. CLINICAL PHARMACOLOGY The steps in the synthesis of the thyroid hormones are controlled by thyrotropin (Thyroid Stimulating Hormone, TSH) secreted by the anterior pituitary. This hormone’s secretion is in turn controlled by a feedback mechanism effected by the thyroid hormones themselves and by thyrotropin releasing hormone (TRH), a tripeptide of hypothalamic origin. Endogenous thyroid hormone secretion is suppressed when exogenous thyroid hormones are administered to euthyroid individuals in excess of the normal gland’s secretion. The mechanisms by which thyroid hormones exert their physiologic action are not well understood. These hormones enhance oxygen consumption by most tissues of the body, increase the basal metabolic rate, and the metabolism of carbohydrates, lipids, and proteins. Thus, they exert a profound influence on every organ system in the body and are of particular importance in the development of the central nervous system. The normal thyroid gland contains approximately 200 mcg of levothyroxine (T4) per gram of gland, and 15 mcg of liothyronine (T3) per gram. The ratio of these two hormones in the circulation does not represent the ratio in the thyroid gland, since about 80% of peripheral liothyronine (T3) comes from monodeiodination of levothyroxine (T4). Peripheral monodeiodination of levothyroxine (T4) at the 5 position (inner ring) also results in the formation of reverse liothyronine (T3), which is calorigenically inactive. Liothyronine (T3) levels are low in the fetus and newborn, in old age, in chronic caloric deprivation, hepatic cirrhosis, renal failure, surgical stress, and chronic illnesses representing what has been called the “T3 thyronine syndrome.” Pharmacokinetics – Animal studies have shown that levothyroxine (T4) is only partially absorbed from the gastrointestinal tract. The degree of absorption is dependent on the vehicle used for its administration and by the character of the intestinal contents, the intestinal flora, including plasma protein, and soluble dietary factors, all of which bind thyroid and thereby make it unavailable for diffusion. Only 41% is absorbed when given in a gelatin capsule as opposed to a 74% absorption when given with an albumin carrier. Depending on other factors, absorption has varied from 48 to 79% of the administered dose. Fasting increases absorption. Malabsorption syndromes, as well as dietary factors, (children’s soybean formula, concomitant use of anionic exchange resins such as cholestyramine) cause excessive fecal loss. Liothyronine (T3) is almost totally absorbed, 95% in 4 hours. The hormones contained in desiccated thyroid extract preparations are absorbed in a manner similar to the synthetic hormones. More than 99% of circulating hormones are bound to serum proteins, including thyroid- binding globulin (TBg), thyroid-binding prealbumin (TBPA), and albumin (TBa), whose capacities and affinities vary for the hormones. The higher affinity of levothyroxine (T4) for both TBg and TBPA as compared to liothyronine (T3) partially explains the higher serum levels and longer half-life of the former hormone. Both protein-bound hormones exist in reverse equilibrium with minute amounts of free hormone, the latter accounting for the metabolic activity. Deiodination of levothyroxine (T4) occurs at a number of sites, including liver, kidney, and other tissues. The conjugated hormone, in the form of glucuronide or sulfate, is found in the bile and gut where it may complete an enterohepatic circulation. 85% of levothyroxine (T4) metabolized daily is deiodinated. INDICATIONS AND USAGE Armour Thyroid (thyroid tablets, USP) are indicated: 1. As replacement or supplemental therapy in patients with hypothyroidism of any etiology, except transient hypothyroidism during the recovery phase of subacute thyroiditis. This category includes cretinism, myxedema, and ordinary hypothyroidism in patients of any age (children, adults, the elderly), or state (including pregnancy); primary hypothyroidism resulting from functional deficiency, primary atrophy, partial or total absence of thyroid gland, or the effects of surgery, radiation, or drugs, with or without the presence of goiter; and secondary (pituitary), or tertiary (hypothalamic) hypothyroidism (See WARNINGS). 2. As pituitary TSH suppressants, in the treatment or prevention of various types of euthyroid goiters, including thyroid nodules, subacute or chronic lymphocytic thyroiditis (Hashimoto’s), multinodular goiter, and in the management of thyroid cancer. CONTRAINDICATIONS Thyroid hormone preparations are generally contraindicated in patients with diagnosed but as yet uncorrected adrenal cortical insufficiency, untreated thyrotoxicosis, and apparent hypersensitivity to any of their active or extraneous constituents. There is no well-documented evidence from the literature, however, of true allergic or idiosyncratic reactions to thyroid hormone. WARNINGS Drugs with thyroid hormone activity, alone or together with other therapeutic agents, have been used for the treatment of obesity. In euthyroid patients, doses within the range of daily hormonal requirements are ineffective for weight reduction. Larger doses may produce serious or even life-threatening manifestations of toxicity, particularly when given in association with sympathomimetic amines such as those used for their anorectic effects. The use of thyroid hormones in the therapy of obesity, alone or combined with other drugs, is unjustified and has been shown to be ineffective. Neither is their use justified for the treatment of male or female infertility unless this condition is accompanied by hypothyroidism. The active ingredient in Armour Thyroid (thyroid tablets, USP) is derived from porcine (pig) thyroid glands of pigs processed for human food consumption and is produced at a facility that also handles bovine (cow) tissues from animals processed for human food consumption. As a result, a potential risk of product contamination with porcine and bovine viral or other adventitious agents cannot be ruled out. No cases of disease transmission associated with the use of Armour Thyroid (thyroid tablets, USP) have been reported. PRECAUTIONS General — Thyroid hormones should be used with great caution in a number of circumstances where the integrity of the cardiovascular system, particularly the coronary arteries, is suspected. These include patients with angina pectoris or the elderly, in whom there is a greater likelihood of occult cardiac disease. In these patients, therapy should be initiated with low doses, i.e., 15-30 mg Armour Thyroid (thyroid tablets, USP). When, in such patients, a euthyroid state can only be reached at the expense of an aggravation of the cardiovascular disease, thyroid hormone dosage should be reduced. Thyroid hormone therapy in patients with concomitant diabetes mellitus or diabetes insipidus or adrenal cortical insufficiency aggravates the intensity of their symptoms. Appropriate adjustments of the various therapeutic measures directed at these concomitant endocrine diseases are required. The therapy of myxedema coma requires simultaneous administration of glucocorticoids (See DOSAGE AND ADMINISTRATION). Hypothyroidism decreases and hyperthyroidism increases the sensitivity to oral anticoagulants. Prothrombin time should be closely monitored in thyroid-treated patients on oral anticoagulants and dosage of the latter agents adjusted on the basis of frequent prothrombin time determinations. In infants, excessive doses of thyroid hormone preparations may produce craniosynostosis. Information for the Patient — Patients on thyroid hormone preparations and parents of children on thyroid therapy should be informed that: 1. Replacement therapy is to be taken essentially for life, with the exception of cases of transient hypothyroidism, usually associated with thyroiditis, and in those patients receiving a therapeutic trial of the drug. 2. They should immediately report during the course of therapy any signs or symptoms of thyroid hormone toxicity, e.g., chest pain, increased pulse rate, palpitations, excessive sweating, heat intolerance, nervousness, or any other unusual event. 3. In case of concomitant diabetes mellitus, the daily dosage of antidiabetic medication may need readjustment as thyroid hormone replacement is achieved. If thyroid medication is stopped, a downward readjustment of the dosage of insulin or oral hypoglycemic agent may be necessary to avoid hypoglycemia. At all times, close monitoring of urinary glucose levels is mandatory in such patients. 4. In case of concomitant oral anticoagulant therapy, the prothrombin time should be measured frequently to determine if the dosage of oral anticoagulants is to be readjusted. 5. Instruct patients to discontinue biotin or any biotin-containing supplements for at least 2 days before thyroid function testing is conducted. 6. Partial loss of hair may be experienced by children in the first few months of thyroid therapy, but this is usually a transient phenomenon and later recovery is usually the rule. Laboratory Tests — Treatment of patients with thyroid hormones requires the periodic assessment of thyroid status by means of appropriate laboratory tests besides the full clinical evaluation. The TSH suppression test can be used to test the effectiveness of any thyroid preparation bearing in mind the relative insensitivity of the infant pituitary to the negative feedback effect of thyroid hormones. Serum T4 levels can be used to test the effectiveness of all thyroid medications except T3. When the total serum T4 is low but TSH is normal, a test specific to assess unbound (free) T4 levels is warranted. Specific measurements of T4 and T3 by competitive protein binding or radioimmunoassay are not influenced by blood levels of organic or inorganic iodine. Drug Interactions — Oral Anticoagulants – Thyroid hormones appear to increase catabolism of vitamin K- dependent clotting factors. If oral anticoagulants are also being given, compensatory increases in clotting factor synthesis are impaired. Patients stabilized on oral anticoagulants who are found to require thyroid replacement therapy should be watched very closely when thyroid is started. If a patient is truly hypothyroid, it is likely that a reduction in anticoagulant dosage will be required. No special precautions appear to be necessary when oral anticoagulant therapy is begun in a patient already stabilized on maintenance thyroid replacement therapy. Insulin or Oral Hypoglycemics – Initiating thyroid replacement therapy may cause increases in insulin or oral hypoglycemic requirements. The effects seen are poorly understood and depend upon a variety of factors such as dose and type of thyroid preparations and endocrine status of the patient. Patients receiving insulin or oral hypoglycemics should be closely watched during initiation of thyroid replacement therapy. Cholestyramine or Colestipol – Cholestyramine or colestipol binds both levothyroxine (T4) and liothyronine (T3) in the intestine, thus impairing absorption of these thyroid hormones. In vitro studies indicate that the binding is not easily removed. Therefore four to five hours should elapse between administration of cholestyramine or colestipol and thyroid hormones. Estrogen, Oral Contraceptives – Estrogens tend to increase serum thyroxine-binding globulin (TBg). In a patient with a nonfunctioning thyroid gland who is receiving thyroid replacement therapy, free levothyroxine (T4) may be decreased when estrogens are started thus increasing thyroid requirements. However, if the patient’s thyroid gland has sufficient function, the decreased free levothyroxine (T4) will result in a compensatory increase in levothyroxine (T4) output by the thyroid. Therefore, patients without a functioning thyroid gland who are on thyroid replacement therapy may need to increase their thyroid dose if estrogens or estrogen-containing oral contraceptives are given. Drug/Laboratory Test Interactions — The following drugs or moieties are known to interfere with laboratory tests performed in patients on thyroid hormone therapy: androgens, corticosteroids, estrogens, oral contraceptives containing estrogens, iodine-containing preparations, and the numerous preparations containing salicylates. 1. Changes in TBg concentration should be taken into consideration in the interpretation of levothyroxine (T4) and liothyronine (T3) values. In such cases, the unbound (free) hormone should be measured. Pregnancy, estrogens, and estrogen-containing oral contraceptives increase TBg concentrations. TBg may also be increased during infectious hepatitis. Decreases in TBg concentrations are observed in nephrosis, acromegaly, and after androgen or corticosteroid therapy. Familial hyper- or hypo- thyroxine-binding-globulinemias have been described. The incidence of TBg deficiency approximates 1 in 9000. The binding of levothyroxine by TBPA is inhibited by salicylates. 2. Biotin supplementation is known to interfere with thyroid hormone immunoassays that are based on a biotin and streptavidin interaction, which may result in erroneous thyroid hormone test results. Stop biotin and biotin-containing supplements for at least 2 days prior to thyroid testing. 3. Medicinal or dietary iodine interferes with all in vivo tests of radio-iodine uptake, producing low uptakes which may not be relative of a true decrease in hormone synthesis. 4. The persistence of clinical and laboratory evidence of hypothyroidism in spite of adequate dosage replacement indicates either poor patient compliance, poor absorption, excessive fecal loss, or inactivity of the preparation. Intracellular resistance to thyroid hormone is quite rare. Carcinogenesis, Mutagenesis, and Impairment of Fertility — A reportedly apparent association between prolonged thyroid therapy and breast cancer has not been confirmed and patients on thyroid for established indications should not discontinue therapy. No confirmatory long-term studies in animals have been performed to evaluate carcinogenic potential, mutagenicity, or impairment of fertility in either males or females. Thyroid hormones do not readily cross the placental barrier. The clinical experience to date does not indicate any adverse effect on fetuses when thyroid hormones are administered to pregnant women. On the basis of current knowledge, thyroid replacement therapy to hypothyroid women should not be discontinued during pregnancy. Nursing Mothers — Minimal amounts of thyroid hormones are excreted in human milk. Thyroid is not associated with serious adverse reactions and does not have a known tumorigenic potential. However, caution should be exercised when thyroid is administered to a nursing woman. Pediatric Use — Pregnant mothers provide little or no thyroid hormone to the fetus. The incidence of congenital hypothyroidism is relatively high (1:4,000) and the hypothyroid fetus would not derive any benefit from the small amounts of hormone crossing the placental barrier. Routine determinations of serum T4 and/or TSH is strongly advised in neonates in view of the deleterious effects of thyroid deficiency on growth and development. Treatment should be initiated immediately upon diagnosis, and maintained for life, unless transient hypothyroidism is suspected; in which case, therapy may be interrupted for 2 to 8 weeks after the age of 3 years to reassess the condition. Cessation of therapy is justified in patients who have maintained a normal TSH during those 2 to 8 weeks. ADVERSE REACTIONS Adverse reactions other than those indicative of hyperthyroidism because of therapeutic overdosage, either initially or during the maintenance period, are rare (See OVERDOSAGE). OVERDOSAGE Signs and Symptoms — Excessive doses of thyroid result in a hypermetabolic state resembling in every respect the condition of endogenous origin. The condition may be self-induced. Treatment of Overdosage — Dosage should be reduced or therapy temporarily discontinued if signs and symptoms of overdosage appear. Treatment may be reinstituted at a lower dosage. In normal individuals, normal hypothalamic-pituitary-thyroid axis function is restored in 6 to 8 weeks after thyroid suppression. Treatment of acute massive thyroid hormone overdosage is aimed at reducing gastrointestinal absorption of the drugs and counteracting central and peripheral effects, mainly those of increased sympathetic activity. Vomiting may be induced initially if further gastrointestinal absorption can reasonably be prevented and barring contraindications such as coma, convulsions, or loss of the gagging reflex. Treatment is symptomatic and supportive. Oxygen may be administered and ventilation maintained. Cardiac glycosides may be indicated if congestive heart failure develops. Measures to control fever, hypoglycemia, or fluid loss should be instituted if needed. Antiadrenergic agents, particularly propranolol, have been used advantageously in the treatment of increased sympathetic activity. Propranolol may be administered intravenously at a dosage of 1 to 3 mg, over a 10-minute period or orally, 80 to 160 mg/day, initially, especially when no contraindications exist for its use. Other adjunctive measures may include administration of cholestyramine to interfere with thyroxine absorption, and glucocorticoids to inhibit conversion of T4 to T3. DOSAGE AND ADMINISTRATION The dosage of thyroid hormones is determined by the indication and must in every case be individualized according to patient response and laboratory findings. Biotin supplementation may interfere with immunoassays for TSH, T4, and T3, resulting in erroneous thyroid hormone test results. Inquire whether patients are taking biotin or biotin-containing supplements. If so, advise them to stop biotin supplementation at least 2 days before assessing TSH and/or T4 levels (see PRECAUTIONS). Thyroid hormones are given orally. In acute, emergency conditions, injectable levothyroxine sodium (T4) may be given intravenously when oral administration is not feasible or desirable, as in the treatment of myxedema coma, or during total parenteral nutrition. Intramuscular administration is not advisable because of reported poor absorption. Hypothyroidism — Therapy is usually instituted using low doses, with increments which depend on the cardiovascular status of the patient. The usual starting dose is 30 mg Armour Thyroid (thyroid tablets, USP), with increments of 15 mg every 2 to 3 weeks. A lower starting dosage, 15 mg/day, is recommended in patients with long-standing myxedema, particularly if cardiovascular impairment is suspected, in which case extreme caution is recommended. The appearance of angina is an indication for a reduction in dosage. Most patients require 60 to 120 mg/day. Failure to respond to doses of 180 mg suggests lack of compliance or malabsorption. Maintenance dosages 60 to 120 mg/day usually result in normal serum T4 and T3 levels. Adequate therapy usually results in normal TSH and T4 levels after 2 to 3 weeks of therapy. Readjustment of thyroid hormone dosage should be made within the first four weeks of therapy, after proper clinical and laboratory evaluations, including serum levels of T4, bound and free, and TSH. Liothyronine (T3) may be used in preference to levothyroxine (T4) during radio-isotope scanning procedures, since induction of hypothyroidism in those cases is more abrupt and can be of shorter duration. It may also be preferred when impairment of peripheral conversion of levothyroxine (T4) and liothyronine (T3) is suspected. Myxedema Coma — Myxedema coma is usually precipitated in the hypothyroid patient of long-standing by intercurrent illness or drugs such as sedatives and anesthetics and should be considered a medical emergency. Therapy should be directed at the correction of electrolyte disturbances and possible infection besides the administration of thyroid hormones. Corticosteroids should be administered routinely. Levothyroxine (T4) and liothyronine (T3) may be administered via a nasogastric tube but the preferred route of administration of both hormones is intravenous. Levothyroxine sodium (T4) is given at a starting dose of 400 mcg (100 mcg/mL) given rapidly, and is usually well tolerated, even in the elderly. This initial dose is followed by daily supplements of 100 to 200 mcg given IV. Normal T4 levels are achieved in 24 hours followed in 3 days by threefold elevation of T3. Oral therapy with thyroid hormone would be resumed as soon as the clinical situation has been stabilized and the patient is able to take oral medication. Thyroid Cancer — Exogenous thyroid hormone may produce regression of metastases from follicular and papillary carcinoma of the thyroid and is used as ancillary therapy of these conditions with radioactive iodine. TSH should be suppressed to low or undetectable levels. Therefore, larger amounts of thyroid hormone than those used for replacement therapy are required. Medullary carcinoma of the thyroid is usually unresponsive to this therapy. Thyroid Suppression Therapy — Administration of thyroid hormone in doses higher than those produced physiologically by the gland results in suppression of the production of endogenous hormone. This is the basis for the thyroid suppression test and is used as an aid in the diagnosis of patients with signs of mild hyperthyroidism in whom base line laboratory tests appear normal, or to demonstrate thyroid gland autonomy in patients with Grave’s ophthalmopathy. 131I uptake is determined before and after the administration of the exogenous hormone. A 50% or greater suppression of uptake indicates a normal thyroid-pituitary axis and thus rules out thyroid gland autonomy. For adults, the usual suppressive dose of levothyroxine (T4) is 1.56 mcg/kg of body weight per day given for 7 to 10 days. These doses usually yield normal serum T4 and T3 levels and lack of response to TSH. Thyroid hormones should be administered cautiously to patients in whom there is strong suspicion of thyroid gland autonomy, in view of the fact that the exogenous hormone effects will be additive to the endogenous source. Pediatric Dosage — Pediatric dosage should follow the recommendations summarized in Table 1. In infants with congenital hypothyroidism, therapy with full doses should be instituted as soon as the diagnosis has been made. Table 1: Recommended Pediatric Dosage for Congenital Hypothyroidism Age Armour Thyroid (thyroid tablets, USP) Dose per day Daily dose per kg of body weight 0-6 months 15-30 mg 4.8-6 mg 6-12 months 30-45 mg 3.6-4.8 mg 1-5 years 45-60 mg 3-3.6 mg 6-12 years 60-90 mg 2.4-3 mg Over 12 years Over 90 mg 1.2-1.8 mg HOW SUPPLIED Armour Thyroid (thyroid tablets, USP) are supplied as follows: 15 mg (1/4 grain) are available in bottles of 100 (NDC 0456-0457-01 or NDC 0456-1045- 01). 30 mg (1/2 grain) are available in bottles of 100 (NDC 0456-0458-01) and unit dose cartons of 100 (NDC 0456-0458-63). 60 mg (1 grain) are available in bottles of 100 (NDC 0456-0459-01) and unit dose cartons of 100 (NDC 0456-0459-63). 90 mg (1 1/2 grain) are available in bottles of 100 (NDC 0456-0460-01). 120 mg (2 grain) are available in bottles of 100 (NDC 0456-0461-01) and unit dose cartons of 100 (NDC 0456-0461-63). 180 mg (3 grain) are available in bottles of 100 (NDC 0456-0462-01). 240 mg (4 grain) are available in bottles of 100 (NDC 0456-0463-01). 300 mg (5 grain) are available in bottles of 100 (NDC 0456-0464-01). The bottles of 100 are special dispensing bottles with child-resistant closures. Armour Thyroid (thyroid tablets, USP) are evenly colored, light tan, round tablets, with convex surfaces. The ¼ grain strength has: One side debossed with a mortar and pestle beneath the letter “A” on the top and TC on the bottom (NDC 0456-0457-01); or One side debossed with a mortar and pestle beneath the letter “A” and the opposite side debossed with TC (NDC 0456-1045-01). Other tablet strengths have one side debossed with a mortar and pestle beneath the letter “A” on the top and strength code letters on the bottom as defined below Strength Code ½ grain TD 1 grain TE 1 ½ grain TJ 2 grain TF 3 grain TG (bisected) 4 grain TH 5 grain TI (bisected) Note: (T3 liothyronine is approximately four times as potent as T4 levothyroxine on a microgram for microgram basis.) Store in a tight container protected from light and moisture. Store between 15°C and 30°C (59°F and 86°F). *Armour Thyroid (thyroid tablets, USP) has not been approved by FDA as a new drug. Distributed by: AbbVie, Inc., North Chicago, IL 60064 © 2024 AbbVie. All rights reserved. ARMOUR is a trademark of Allergan Sales, LLC, an AbbVie company. Revised: March 2024 20084309 PRINCIPAL DISPLAY PANEL NDC 0456-0457-01 Armour Thyroid (thyroid tablets, USP) ¼ GRAIN (15 mg) Each tablet contains: levothyroxine (T ) 9.5 mcg liothyronine (T ) 2.25 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0458-01 Armour Thyroid (thyroid tablets, USP) ½ GRAIN (30 mg) Each tablet contains: levothyroxine (T ) 19 mcg liothyronine (T ) 4.5 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0459-01 Armour Thyroid (thyroid tablets, USP) 1 GRAIN (60 mg) Each tablet contains: levothyroxine (T ) 38 mcg liothyronine (T ) 9 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0460-01 Armour Thyroid (thyroid tablets, USP) 1½ GRAIN (90 mg) Each tablet contains: levothyroxine (T ) 57 mcg liothyronine (T ) 13.5 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0461-01 Armour Thyroid (thyroid tablets, USP) 2 GRAIN (120 mg) Each tablet contains: levothyroxine (T ) 76 mcg liothyronine (T ) 18 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0462-01 Armour Thyroid (thyroid tablets, USP) 3 GRAIN (180 mg) Each tablet contains: levothyroxine (T ) 114 mcg liothyronine (T ) 27 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0463-01 Armour Thyroid (thyroid tablets, USP) 4 GRAIN (240 mg) Each tablet contains: levothyroxine (T ) 152 mcg liothyronine (T ) 36 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-0464-01 Armour Thyroid (thyroid tablets, USP) 5 GRAIN (300 mg) Each tablet contains: levothyroxine (T ) 190 mcg liothyronine (T ) 45 mcg 100 TABLETS abbvie Rx only ® 4 3 PRINCIPAL DISPLAY PANEL NDC 0456-1045-01 Armour Thyroid (thyroid tablets, USP) 1/4 GRAIN (15 mg) ARMOUR THYROID ® thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0457 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 15 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 5mm Flavor Imprint Code A;TC Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0457- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-1045 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 15 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 5mm Flavor Imprint Code A;TC Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-1045- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0458 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 30 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 6mm Flavor Imprint Code A;TD Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456- 0458-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 2 NDC:0456- 0458-63 10 in 1 BOX, UNIT-DOSE 04/01/1996 2 NDC:0456- 0458-11 10 in 1 BLISTER PACK; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0459 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 60 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 7mm Flavor Imprint Code A;TE Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456- 0459-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 2 NDC:0456- 0459-63 10 in 1 BOX, UNIT-DOSE 04/01/1996 2 NDC:0456- 0459-11 10 in 1 BLISTER PACK; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0460 Route of Administration ORAL Active Ingredient/Active Moiety Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 90 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 9mm Flavor Imprint Code A;TJ Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0460- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0461 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 120 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 10mm Flavor Imprint Code A;TF Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456- 0461-01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 2 NDC:0456- 0461-63 10 in 1 BOX, UNIT-DOSE 04/01/1996 2 NDC:0456- 0461-11 10 in 1 BLISTER PACK; Type 0: Not a Combination Product Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0462 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 180 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 10mm Flavor Imprint Code A;TG Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0462- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0463 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 240 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 11mm Flavor Imprint Code A;TH Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0463- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 ARMOUR THYROID thyroid, porcine tablet Product Information Product Type HUMAN PRESCRIPTION DRUG Item Code (Source) NDC:0456-0464 Route of Administration ORAL Active Ingredient/Active Moiety Ingredient Name Basis of Strength Strength SUS SCROFA THYROID (UNII: 6RV024OAUQ) (SUS SCROFA THYROID - UNII:6RV024OAUQ) SUS SCROFA THYROID 300 mg Inactive Ingredients Ingredient Name Strength CALCIUM STEARATE (UNII: 776XM7047L) DEXTROSE, UNSPECIFIED FORM (UNII: IY9XDZ 35W2) CELLULOSE, MICROCRYSTALLINE (UNII: OP1R32D61U) SODIUM STARCH GLYCOLATE TYPE A (UNII: H8AV0SQX4D) Allergan, Inc. Product Characteristics Color brown (light tan) Score no s core Shape ROUND (ROUND) Size 13mm Flavor Imprint Code A;TI Contains Packaging # Item Code Package Description Marketing Start Date Marketing End Date 1 NDC:0456-0464- 01 100 in 1 BOTTLE; Type 0: Not a Combination Product 04/01/1996 Marketing Information Marketing Category Application Number or Monograph Citation Marketing Start Date Marketing End Date unapproved drug other 04/01/1996 Labeler - Allergan, Inc. (144796497) Revised: 3/2024

Et intervju med David Derry, M.D., Ph.D. Historien om skjoldbrusktesting, hvorfor TSH-testen må forlates, og tilbakevendingen til symptombasert skjoldbruskdiagnose og behandling. Skrevet av Mary Shomon / Thyroid Patient Advocacy Originalspråk: Engelsk Nesten hver konvensjonell diskusjon om skjoldbruskkjertelsykdom fokuserer på bruken av thyroideastimulerende hormon (TSH) som den diagnostiske "gullstandarden" for skjoldbruskkjertelsykdom. TSH brukes nesten utelukkende av de fleste konvensjonelle leger som et middel til å diagnostisere skjoldbruskkjertelsykdom, uavhengig av symptomer. Vanligvis, hvis TSH-nivået er over normalområdet, blir en pasient diagnostisert som hypothyroid, og TSH-nivåer under normalområdet tolkes som hyperthyroid. Men er TSH-testen og referansen "normalområde" nøyaktig? Bør diagnose av skjoldbruskkjertelsykdom først og fremst være basert på denne ene testen? Noen eksperter sier nei. Dr. A P Weetman, professor i medisin, skrev i artikkelen «Fortnightly review: Hypothyroidism: screening and subclinical disease», som dukket opp i 19. april 1997-utgaven av British Medical Journal, følgende banebrytende uttalelse: "...selv innenfor referanseområdet på rundt 0,5-4,5 mU/l, var en høy thyreoideastimulerende hormonkonsentrasjon (>2 mU/l) assosiert med økt risiko for fremtidig hypotyreose. Den enkleste forklaringen er at skjoldbruskkjertelsykdom er så vanlig at mange mennesker som er disponert for skjoldbruskkjertelsvikt er inkludert i et laboratoriums referansepopulasjon, noe som reiser spørsmålet om tyroksin-erstatning er tilstrekkelig hos pasienter med nivåer av skjoldbruskkjertelstimulerende hormon over 2 mU/l." Som svar til Dr. Weetman, svarte David Derry M.D., Ph.D., en skjoldkjertelekspert og forsker, basert i Victoria, British Columbia: "Hvorfor følger vi en test som ikke har noen sammenheng med klinisk presentasjon? Tyreoidologene har ved konsensus bestemt at denne testen er den mest nyttige for å følge behandling når den faktisk ikke er relatert til hvordan pasienten har det. Konsekvensene av dette har vært forferdelige. Seks år etter deres konsensusbeslutning dukket kronisk tretthet og fibromyalgi opp. Disse er begge hypothyroide tilstander. Men fordi deres TSH var normal, har de ikke blitt behandlet. TSH må skrotes og medisinstudenter igjen opplæres i hvordan man klinisk gjenkjenner lav skjoldkjertelfunksjon.» Dette provoserende svaret var hvordan Dr. Derry ble oppmerksom på mange skjoldbruskkjertelpasienter, og intervjueren Mary Shomon, About's skjoldbruskkjertelguide. I dette intervjuet deler Dr. Derry sine fascinerende og innovative ideer om hvorfor han mener at TSH-testen må forlates. Dette intervjuet ble gjennomført i juli 2000. Mary Shomon: Først, Dr. Derry, kan du fortelle oss litt om din medisinske bakgrunn og interesse for testing og behandling av skjoldbruskkjertelen? David Derry: Jeg har alltid vært interessert i medisinsk forskning. Jeg ble uteksaminert med en medisinsk grad fra University of British Columbia, Canada i Vancouver i 1962. Jeg studerte ved Toronto General Hospital. Derfra dro jeg til McGill University og gikk inn i et fireårig program for å få doktorgraden min i biokjemi og mer spesifikt i nevrokjemi ved instituttet satt opp av Wilder Penfield kalt Montreal Neurological Institute i Montreal. I 1967 ble jeg uteksaminert med en doktorgrad i biokjemi fra McGill. Jeg ble ansatt av avdelingen for farmakologi ved University of Toronto Medical School som assisterende professor. I fem år drev jeg grunnleggende biokjemisk forskning og underviste medisinstudenter, odontologistudenter og farmasistudenter. Ikke lenge etter at jeg ankom Toronto ble jeg stipendiat ved Medical Research Council of Canada. Det vil si at lønnen min ble betalt av The Medical Research Council of Canada for å gjøre ren forskning i fem år. Samtidig jobbet jeg i helgene med ansvaret og den eneste legen på et stort psykiatrisk sykehus med 900 sengeplasser kalt Lakeshore Psychiatric Hospital. I mellomtiden omtrent da (1970) hadde jeg en omorganisering av min hjemlige status. Jeg endte opp med å gifte meg med min nåværende kone og fikk tre barn til. Jeg hadde to egne. Alle barna var mellom 4 og 9 år. Det fantes ingen mulighet for at lønnen til en assisterende professor i farmakologi ved University of Toronto skulle være i stand til å betale for og oppdra fem små barn. Etter at de juridiske aspektene var avgjort, gikk min kone og jeg, de fem barna og en stor labrador retriever, ombord på en 747 til Victoria, British Columbia. I løpet av to uker begynte jeg med allmennpraksis. Da jeg kom tilbake til allmennpraksisen hadde jeg i tankene et ordtak jeg tilskriver Dr. Wilder Penfield som var "Hvis du lytter nøye til en pasient vil pasienten fortelle deg diagnosen, og hvis du lytter enda mer nøye vil de fortelle deg den mest passende behandlingen». Før jeg gikk tilbake til praksis hadde jeg tatt kurs i mellommenneskelige relasjoner og hvordan man kan kommunisere og lytte bedre. Siden jeg begynte i allmennmedisin har jeg tatt flere kurs i personlig utvikling. Tanken min var å lære mer om hvordan jeg kan lytte nøye og hvordan jeg kan få min personlighet (ego) ut av veien for samtalen med pasienten. Fordi jeg var bevæpnet med denne tilnærmingen, har jeg kunnet lære mye de siste 28 årene i praksis. Etter ca 3-4 år i praksis tenkte jeg at jeg skulle begynne å gjøre min egen forskning. Jeg begynte med vitaminer. Blant mange andre emner underviste jeg i vitaminer ved University of Toronto, og da Dr. Linus Paulings bok om vitamin C og kreft kom ut i 1970 ble jeg bedt av Det medisinske fakultet om å presentere det vesentlige materialet i boken for rundt 300 fakultetsmedlemmer. og studenter. Derfor var vitaminer, deres profylaktiske og terapeutiske bruk et godt sted for meg å begynne å forske. Så jeg undersøkte bruken av vitaminer for alle slags sykdommer. Til slutt, etter omtrent 10 år, hadde jeg ganske godt uttømt alle aspekter av den terapeutiske bruken av vitaminer jeg kunne tenke meg. Da visste jeg hva du kunne gjøre og ikke kunne gjøre med vitaminer. De fleste av pasientene var bare så glade for å hjelpe meg med dette, og de som ble bedre var veldig takknemlige. Siden da har jeg sakte de siste 15-20 årene utviklet en interesse for skjoldbruskkjertelproblemer. Det er årsaker til min interesse for skjoldbruskkjertelen som er for lange å si. Etter hvert fikk jeg kopier av all relevant skjoldbruskkjertellitteratur tilbake til 1883 Committee on Myxedema. Jeg har et enormt bibliotek om skjoldbruskkjertellitteraturen bestående av rundt 5000 opptrykk og bøker. Alle de gamle lærebøkene kopierte jeg og oppbevarer dem i biblioteket til mitt bruk. Alt dette er datastyrt selvfølgelig. Konsensus fra tyreoidologer bestemte i 1973 at TSH var blodprøven de hadde lett etter gjennom årene. Dette var omtrent to år etter at jeg begynte å praktisere. Etter å ha blitt lært hvordan man diagnostiserer hypothyroid tilstander klinisk, var jeg i stand til å se for å se hva forholdet mellom TSH var til utbruddet av hypotyreose. Det jeg fant ut var at mange mennesker ville utvikle klassiske tegn og symptomer på hypotyreose, men TSH var treg til å bli unormal, stige og bekrefte den kliniske diagnosen. Noen ganger gjorde den det aldri. Til slutt begynte jeg å behandle pasienter med skjoldbruskkjertelen på den vanlige måten jeg ble lært. Jeg kunne ikke se hvorfor jeg måtte vente på at TSH skulle stige for at jeg skulle kunne behandle dem. Hovedingrediensen i skjoldbruskkjertelhormon, som skiller det fra andre molekyler av lignende størrelse (molekylstørrelse), var elementet som laget skjoldbruskkjertelhormon, nemlig jod. Så jeg gjorde et grundig søk i litteraturen om jod. Denne undersøkelsen førte til at jeg prøvde å bruke jod og skjoldbruskkjertelen terapeutisk. TSH hadde fått all forskning på terapeutisk bruk av begge disse stoffene til å stoppe døden. Min biokjemiske og farmakologiske bakgrunn har tillatt meg å søke i områder av litteraturen som er umulig for en vanlig lege eller til og med en spesialist å utforske. Hvis du husker, var det lenge før legestanden innrømmet at det var to nye sykdommer som dukket opp i verden som ikke var der før. Kronisk tretthet og fibromyalgi var ikke-eksisterende før 1980. Dette er syv år etter konsensusmøtet i 1973. Så hvor kom disse to nye sykdommene fra? Symptomene og tegnene på kronisk tretthet og fibromyalgi ble beskrevet i litteraturen på 1930-tallet som en måte lav skjoldbruskkjertel kan uttrykkes på. Behandlet tidlig ble det lett fikset med skjoldkjertelekstrakt i tilstrekkelige doser. Men allerede da hadde klinikerne lagt merke til at hvis en pasient har lav skjoldkjertelfunksjon (kronisk tretthet og fibromyalgi) for lenge, så ble det vanskeligere å reversere alle tegn og symptomer uavhengig av hva de var. Mary Shomon: Hvorfor tror du at tyreoidologer har bestemt at TSH-testen er den mest nyttige - eller i mange tilfeller - den eneste testen for skjoldbruskkjertelproblemer, kontra en pasients kliniske symptomer? Hvordan tror du dette har blitt ansett som "gullstandarden" for skjoldbruskkjerteldiagnose og -behandling? David Derry: Tyreoidologene har lett etter en pålitelig test for skjoldbruskkjertelfunksjon siden begynnelsen av århundret. De første viktige var Basal Metabolic Rate, kolesterolet og kreatinfosfokinasen. (CK). Disse ble hovedsakelig brukt frem til ca 1960. Hadde du høyt kolesterol i første halvdel av århundret fikk du skjoldkjertelekstrakt for å senke det til det normale. Detaljer om bruk av denne behandlingsmetoden ble fortsatt beskrevet på 1950-tallet. Basal Metabolic rate ble populær på 30- og 40-tallet, og nesten alle kontorer hadde en maskin for å måle den. Det fungerte ganske bra, men var utsatt for vanskeligheter med tolkning og forstyrrelser av emosjonelle faktorer. Imidlertid er det fortsatt den eneste testen som faktisk måler effekten av skjoldkjertelmedisin på menneskekroppen. På 1940-tallet ble radioaktivt jod tilgjengelig fra Tennessee Valley Atomic Energy Complex. Derfor kan jodmetabolismen studeres nærmere. Det radioaktive jodopptaket i skjoldbruskkjertelen ble en hyppig brukt test, som ble sagt å være ufeilbarlig som alle de andre da de først ankom. Hver gang det var en ny test ble den erklært å være pålitelig for å fortelle om en person var hyperthyroid eller hypothyroid, men som med alle tidligere tester viste det seg å ikke være klinisk anvendelig i alle tilfeller. På 1960-tallet, da jeg studerte medisin, ble PBI (Protein bound jod) kunngjort som den eneste nødvendige testen, når den var lav hadde du hypotyreose og når den var høy hadde du hypertyreose. Dette sto skrevet i noen av datidens lærebøker. Til slutt gikk det med denne testen som med resten - nyttig noen ganger - men stemte ikke alltid med de kliniske funnene. Deretter kom T4 eller total tyroksin i blodet som er det frie og proteinbundne tyroksinet målt sammen. Dette ble også hyllet som langt overlegent PBI, men det gikk også veien for resten av testene - som ikke pålitelig nok. Til slutt kom TSH på slutten av 60-tallet og ble skrytt av som det endelige svaret. TSH var ikke bare i stand til å levere alle skjoldbruskkjerteldiagnosene, men den kunne også brukes til å overvåke terapi. I løpet av de følgende tjue årene ble TSH gjort mer og mer følsom, og på grunn av disse forbedringene ble det enda mer antatt at det var det endelige svaret for skjoldbruskkjerteldiagnose og behandling. Men siden TSH var så følsom for oralt gitt skjoldbruskkjertelhormon, betydde det at bokstavelig talt alle kom til å ende opp med en lav dose sammenlignet med tidligere doser. De nye dosene var omtrent en tredjedel av dosen som hadde blitt funnet å være klinisk effektiv for hver pasient i åtti år før TSH. TSH hadde en ring av vitenskapelig strenghet for de som har en smått med kunnskap om skjoldbruskkjertelens metabolisme. Det var en del av hypofysens tilbakekoblingsmekanisme for å overvåke produksjonen av skjoldbruskkjertelen. Det er ingen tvil om at den gjør denne jobben. Men dessverre har TSH-verdien ingen klinisk korrelasjon bortsett fra i absolutte ekstremer med de kliniske tegnene eller symptomene til pasienten. Årsakene til dette er komplekse, og jeg skal bare forklare ett aspekt, men det er andre viktige faktorer. Til å begynne med styres skjoldbruskmetabolismen lokalt i vevet av hvert organ. Det vil si at hjernen har én mekanisme for å kontrollere mengden skjoldbruskkjertelen som er tilgjengelig for hjernen, men den er forskjellig fra andre vev som leveren. Det er mange mekanismer som hvert vev kontrollerer mengden av skjoldbruskhormon som kommer inn i vevene. Men for å diskutere en: det er et enzym i vevet som avjoderer (tar ett jod av tyroksin T4) og lager T3 eller trijodtyronin. Disse enzymene kalles deiodinaser. Hvert vev har forskjellige typer deiodinaser. For bare å gi deg ett eksempel: Hvis du sulter dyr og studerer deiodinasene i hjernen og leveren, finner du at aktiviteten i hjernens deiodinaser øker med 10 ganger samtidig som leverdeiodinasene går ned – ikke opp. Denne mekanismen er åpenbart ment å bevare hjernens funksjon under sultforhold og ikke metabolisere for mye skjoldbruskkjertelhormon i leveren. Derfor er kontrollen av skjoldbruskkjertelens metabolisme i hvert enkelt vev. Problemet med dette er - hvis et vev trenger mer (for eksempel hjernen med depresjon) er det ingen måte for hjernen å signalisere skjoldbruskkjertelen at den trenger mer sendt opp til den. Skjoldbruskkjertelen fortsetter lystig å sende ut samme mengde hormon. Så pasienten kan ha symptomer relatert til lav skjoldkjertelfunksjon i hjernen (for eksempel), men skjoldbruskkjertelen gjør ikke noe med det. Men hvis du gir skjoldbruskkjertelhormoner i tilstrekkelig dose, vil hjernesymptomene forsvinne. I mellomtiden tilpasser de andre vev og organer seg til de økte sirkulerende hormonene som du har brukt til å fikse hjernen med. Tilpasningen av vevet til forskjellige nivåer av sirkulerende hormoner er vist i litteraturen. Symptomene på lav skjoldbruskkjertelfunksjon, som er mange og uttrykkes varierende, kan være relatert til ethvert organ eller system i kroppen og avhenger delvis av personens gener. Men på grunn av all-inclusiveness av TSH medisinstudenter blir ikke undervist eller bare overfladisk undervist i symptomene på lav skjoldbruskkjertel. TSH var "vitenskapelig" og inneholdt alle svarene på skjoldbruskkjertelsykdom. Hvis du ikke har gjennomlevd flere versjoner av den ultimate testen for skjoldbruskkjertelen, er det vanskeligere å forstå dette fenomenet. Mary Shomon: Hvis, som Dr. Weetman foreslår, laboratoriets referanseområde for "normal" TSH inkluderer personer som er i ferd med å utvikle hypotyreose, føler du at selve referanseområdet bør beregnes på nytt? David Derry: Dette forslaget stemmer overens med det jeg har sagt, nemlig at TSH kan ligge langt bak progresjonen til skjoldbruskkjertelen. Et tydelig tilfelle jeg husker er en dame som begynte å miste håret i en alder av 26 og hadde mistet alt da hun var 35, men TSH økte ikke før hun var 48. Da steg TSH veldig høyt for første gang. (TSH var flere hundre). Hun ble behandlet for en hjertesykdom på det tidspunktet, men da kardiologen så TSH, sa han "bare behandle den lave skjoldbruskkjertelfunksjonen, og hjerteproblemene hennes vil forsvinne". Han hadde rett. Håret hennes har ikke vokst ut enda. Hun har tatt skjoldkjertelekstrakt i ca 1 år nå. Så hennes TSH var forsinket i forhold til symptomene og tegnene hennes med 22 år. I noen tilfeller ser det ut til at TSH aldri stiger og bekrefter den kliniske diagnosen. Det er vanskelig å visualisere bruk av TSH når, som Dr. Weetman har sagt, folk kan ha lav skjoldbruskkjertelfunksjon med normal TSH. Sannheten er at det ikke er noen sammenheng mellom TSH og hvordan folk har det. Dr. Anthony Toft har uttalt dette i bibelen til thyroidologi Werner og Ingbars "TheThyroid" i 1991. Jeg har sitert denne referansen i mitt svar. Dr Weetman har også sagt i et svar på nettet til BMJ-artikkelen fra mai 2000-artikkelen av Denis StJ. O'Reilly på "Tester for skjoldbruskkjertelfunksjonen_tid for en revurdering" at han tror at en pasient kan ha en dyp hypotyreose uten noen tegn eller symptomer. Dette er feil. Å følge TSH mens du behandler noen for lav skjoldbrusk vil også føre til underbehandling av pasienten. Hypofysecellene, som har TSH i seg, er de mest følsomme cellene i kroppen som sirkulerer skjoldbruskkjertelhormon. Derfor når man behandler hypotyreose ved å følge TSH og prøve å gjøre det normalt, er hypofysecellene glade, men resten av kroppen er forkortet med en betydelig mengde. Jeg nevnte også i mitt svar til den samme artikkelen at normaldosen kom til av alle de beste klinikerne i verden over 80 års erfaring var mellom 200 og 400 mikrogram Eltroxine. Men noen trenger mer. For tiden behandlede pasienter er gjennomsnittlig omtrent 100 mikrogram, som er omtrent en tredjedel av dosen som har vært kjent i et århundre for å hjelpe pasienter tilbake til det normale. Langtidsstudier fant ingen forskjell i noen sykdom mellom normale mennesker og personer som tok skjoldbruskkjertelen ved høyere doser. Nyere studier har bekreftet denne oppfatningen. Slutten av denne tilnærmingen til metoden for behandling av hypotyreose ble dokumentert av professor R. Hoffenberg i introduksjonen til hans todelte artikkel om hypertyreose i British Medical Journal 1974. Han reflekterte over en levetid med behandling av skjoldbruskkjertelpasienter, og nevner at hans personlige registrering av mengden av skjoldbruskkjertelen han trengte å gi til en pasient for å få dem til å føle seg riktig, var 29 korn av uttørket skjoldbruskkjertel. som representerer omtrent 1700 mg uttørket skjoldbruskkjertel som vil tilsvare omtrent 2900 mikrogram Eltroxine. Denne høyt respekterte tyreoidologen hadde brukt et helt liv på å behandle skjoldbruskkjertelpasienter, må ha utarbeidet papiret og fått det akseptert i løpet av 1973 da konsensusmøtet om TSH fant sted. Alt dette betyr at selv om pasienten med kronisk utmattelse har et unormalt TSH, vil behandlingen være utilstrekkelig for å gjøre dem friske igjen. Tidligere klinikere (før TSH) var kloke og veldig observante og var i stand til å diagnostisere og behandle hypotyreose riktig uten TSH i 80 år – hvorfor trenger vi det nå? De ville være forferdet over den totale manglende diagnosen kronisk tretthet og fibromyalgi. Behandlingen av skjoldbruskkjertelkreft før TSH innebar å gi den maksimalt tolererte dosen av skjoldbruskkjertelen for å stoppe kreften. Det ble da kalt en subtoksisk dose. Det vil si at dosen av skjoldbruskkjertelen vil bli hevet inntil noen toksiske symptomer oppsto, deretter vil dosen senkes litt for å fjerne symptomene som for mye svette eller takykardi. Den nåværende behandlingen av skjoldbruskkjertelkreftpasienter får bare nok til å undertrykke TSH, som vanligvis er mye lavere. Ingenting uheldig skjedde med disse pasientene fra tiden før TSH på grunn av denne høyere skjoldbruskdosen. Mary Shomon: Du indikerte at du føler kronisk tretthet og fibromyalgi er begge hypotyreoidea tilstander. Det er noen leger som føler at disse to tilstandene er manifestasjoner av vanskelig å diagnostisere hypotyreose, og atter andre studier hevder at det ikke er noen sammenheng. Kan du forklare hvorfor du føler at det er en sammenheng mellom disse forholdene? David Derry: I mange år støttet litteraturen (før TSH) det faktum at hvis symptomene dine reagerte på skjoldbruskkjertelhormon, hadde du lav skjoldbruskkjertel, men spesielt hvis du tok personen av skjoldbruskkjertelen og symptomene kom tilbake. Mine egne pasienter som utvikler kronisk tretthet eller fibromyalgi, jeg behandler dem med skjoldbruskkjertelen og alle – og jeg mener alle – symptomene deres forsvinner. Hvis jeg stopper skjoldbruskkjertelen eller hvis de stopper den av en eller annen grunn, begynner alle symptomene å sakte komme tilbake i løpet av de påfølgende månedene. Du kan spørre om jeg tar skjoldbruskkjertelfunksjonstester? Svaret er ja, om ikke av annen grunn at jeg er nysgjerrig på å vite hvordan de ser ut i møte med pasientens åpenbare kliniske diagnose. De andre pasientene som kommer til meg utenfra min praksis svarer omtrent i forhold til hvor lenge de har hatt det. Men jeg har hatt mange hyggelige overraskelser av mennesker som er sterkt funksjonshemmet av fibromyalgi eller kronisk tretthet i seks år eller mer som sakte over 6 måneder til et år forsvinner helt. Det er selvfølgelig en fryd å se dette skje. Mary Shomon: Føler du at TSH – eller TRH, T4/T3, antistoffer eller omvendt T3 – tester har noen plass i skjoldbrusk diagnose og behandling, eller mener du at diagnose og behandling utelukkende bør være basert på symptomer. David Derry: Et sted TSH har vært nyttig er å teste nyfødte babyer. TSH som støttes av gratis T4 eller Total T4 forteller deg raskt at babyen har et alvorlig problem som må behandles umiddelbart. Dette sier ikke at TSH er ufeilbarlig i dette tilfellet, men i det minste når det er unormalt, vet du at du har et alvorlig problem. Et fenomenalt antall skjoldbruskkjertelfunksjonstester bestilles av leger i dag, men det er usannsynlig at det har hjulpet så mye ettersom legene har ignorert symptomene på lav skjoldbruskkjertel som så mange pasienter klager over. Mary Shomon: Hva er de vanligste symptomene på klinisk hypotyreose du har funnet mest nyttige for å stille en diagnose? David Derry: Jeg holdt et foredrag om skjoldbruskkjertelen for omtrent tre år siden og diskuterte dette emnet. Listen over tegn og symptomer fortsetter å vokse etter hvert som jeg lærer mer. De fleste vil ha en eller annen form for tretthet, men det er en gruppe som har høy effekt (les viljestyrke) og lav skjoldbruskkjertel. Disse pasientene er ikke alltid tynne. Et godt eksempel jeg hadde var en 19 år gammel ballettdanser, mens hun danset for et nasjonalt ballettkompani, begynte å se en rådgiver for depresjon. Hun fortsatte å danse med selskapet. Det er ingen måte en person som er fysisk sunn og en alder uten tidligere historie kan være deprimert bortsett fra lav skjoldbruskkjertel. Men mistankene vil bli forsterket når du vet at moren og søsteren hennes har lav skjoldbruskkjerteltilstand. TSH var hevet over normalen, men kuren var den samme uavhengig av om TSH var unormal eller ikke. Hun har vært helt frisk siden den lave skjoldbruskkjertelen ble korrigert. Alle ballettdansere har enormt driv og selvkontroll, derfor kan de ignorere mange symptomer og fortsette. Så personer med sterk viljestyrke kan ignorere mange symptomer og tegn i lang tid. For å sitere Dr. George Crile om hypothyroidisme fra læreboken hans i 1932 om The thyroid and its diseases. «I det avanserte stadiet av sykdommen kan pasienten klage over nesten alle symptomer som kan skyldes lavt stoffskifte. Et sammendrag av litteraturen viser at symptomer som kan refereres til hvert organ i kroppen, har blitt tilskrevet skjoldbruskkjertelmangel og har blitt lindret ved administrering av skjoldbruskkjertelekstrakt." Jeg har nå en enorm organisert liste over hypothyroidsymptomer som jeg ikke vil belaste deg med. Opprinnelig ble den laget for min forelesning, men jeg har lagt til den sakte siden jeg ser nye tegn og symptomer forsvinne med terapi. Mennesker som har hatt forferdelige barndomsopplevelser (seksuelle overgrep, fysiske overgrep, personlige tragedier osv.) uansett grunn har endret skjoldbruskkjertelens metabolisme. De er mer komplekse å behandle. De er forskjellige fra alle andre biokjemisk og farmakologisk. Skylden for de fleste av deres gjenværende vanskeligheter er ikke hjernen og sinnet deres, men kjemien deres. Jeg tror også andre områder av biokjemien deres ikke er normale. Jeg tror ikke dette har blitt generelt anerkjent ennå. Mary Shomon: Hvilken type thyroidhormonerstatningsterapi foretrekker du? Levotyroksin, levotyroksin pluss T3, eller naturlig skjoldbruskhormonerstatning, og hvorfor? David Derry: Jeg bruker noen av de ovennevnte. I Canada har vi bare Eltroxine (levotyroksin) eller uttørket skjoldbruskkjertel (Parke-Davis). T3 er tilgjengelig gjennom spesialapotek, men er ikke like lett tilgjengelig som i USA. Hvis jeg ikke får den responsen jeg ser etter, vil jeg ofte bytte begge veier for å prøve å gjøre pasienten bedre. Mary Shomon: Trener du for øyeblikket? Hvordan kan pasienter avtale å se deg? Gjør du telefonkonsultasjoner? David Derry: Jeg har ingen intensjoner om å trekke meg i nær fremtid. Siden jeg holdt mine to forelesninger for tre år siden om brystkreft og skjoldbruskkjertelen har jeg fått nærmere 2000 nye pasienter. Heldigvis for meg har jeg vært i stand til å hjelpe de fleste av dem, så jeg trenger ikke fortsette å se dem. En god del pasienter kommer ganske langt. Jeg har en haug med pasienter som kommer fra Alberta, og en av disse er en ung dame fra Calgary som flyr til Victoria for hver avtale. Alle som ønsker å komme kan gjøre det ved å bestille gjennom kontoret, på 250 478-8388. Jeg ville blitt for oversvømmet til å svare mye over telefonen. Jeg er også sikker på at jeg ikke kunne diagnostisere og eller behandle noen uten å møte dem. Jeg må følge folk i flere måneder etter å ha sett dem – men ikke ofte etter det – siden skjoldbruskkjertelen jobber så sakte at du må gi det tid. For tiden skriver jeg en bok om brystkreft. Forhåpentligvis vil det være ferdig innen årsskiftet eller før. Etter brystkreftboka skal jeg skrive en om dette emnet. Kontaktinformasjon: David M. Derry M.D., Ph.D. E-Mail dderry@shaw.ca See Dr. Derry’s Biographical Information and Chronological Curriculum Vitae

Skrevet av Dr. Ray Peat, 2006 Originalspråk: Engelsk I. Respiratorisk-metabolsk defekt II. 50 år med kommersielt motivert svindel III. Tester og "fritt hormon-hypotesen" IV. Hendelser i vevet V. Terapier VI. Diagnose I. Respirasjonsdefekt Broda Barnes, for mer enn 60 år siden, oppsummerte de viktigste effektene av hypotyreose veldig godt da han påpekte at hvis hypotyreoide mennesker ikke dør som unge av infeksjonssykdommer, feks tuberkulose, dør de litt senere av kreft eller hjertesykdom. Han gjorde sin doktorgradsforskning ved University of Chicago, bare noen få år etter at Otto Warburg i Tyskland hadde demonstrert rollen til en "åndedrettsdefekt" i kreft. På det tidspunktet Barnes forsket, ble hypotyreose diagnostisert på grunnlag av lavt basalt metabolsk nivå, noe som betyr at bare en liten mengde oksygen var nødvendig for å opprettholde liv. Denne mangelen på oksygenforbruk involverte det samme enzymsystemet som Warburg studerte i kreftceller. Barnes eksperimenterte på kaniner, og fant ut at når skjoldbruskkjertlene deres ble fjernet, utviklet de åreforkalkning, akkurat som hypothyroide mennesker gjorde. På midten av 1930-tallet var det allment kjent at hypotyreose fører til at kolesterolnivået i blodet øker; hyperkolesterolemi var et diagnostisk tegn på hypotyreose. Ved å gi et skjoldbruskkjerteltilskudd kom blodkolesterolet ned til det normale akkurat som den basale metabolske hastigheten økte til normal hastighet. Biologien til aterosklerotisk hjertesykdom ble i utgangspunktet løst før andre verdenskrig. Mange andre sykdommer er nå kjent for å være forårsaket av luftveisdefekter. Betennelse, stress, immunsvikt, autoimmunitet, utviklings- og degenerative sykdommer og aldring involverer alle betydelig unormale oksidative prosesser. Bare kort oksygenmangel utløser prosesser som fører til lipidperoksidasjon, og produserer en kjede av andre oksidative reaksjoner når oksygenet gjenopprettes. Den eneste effektive måten å stoppe lipidperoksidasjon på er å gjenopprette normal respirasjon. Nå som dusinvis av sykdommer er kjent for å involvere defekt respirasjon, blir ideen om skjoldbruskkjertelens ekstremt brede spekter av handlinger lettere å akseptere. II. 50 år med svindel Frem til andre verdenskrig ble hypotyreose diagnostisert på grunnlag av BMR (basal metabolic rate) og en stor gruppe tegn og symptomer. På slutten av 1940-tallet førte promotering av den (biologisk upassende) PBI (proteinbundet jod) blodprøven i USA til konseptet at bare 5 % av befolkningen var hypothyroide, og at de 40 % identifisert med "foreldede" metoder var enten normale, eller led av andre problemer som lathet og overspising, eller "genetisk mottakelighet" for sykdom. I samme periode ble tyroksin tilgjengelig, og hos friske unge menn virket det "akkurat som skjoldbruskkjertelhormonet". Eldre behandlere erkjente at det ikke metabolsk sett var det samme som det tradisjonelle skjoldbruskkjertelstoffet, spesielt for kvinner og alvorlig hypothyroide pasienter. Men markedsføring og dennes innflytelse på medisinsk utdanning førte til den falske ideen om at Armour thyroid USP ikke var riktig standardisert, og at visse tyroksinprodukter var det; til tross for at begge disse påstandene ble vist å være falske. På 1960-tallet ble PBI-testen bevist å være irrelevant for diagnosen hypotyreose, men doktrinen om kun 5% hypotyreose i befolkningen ble ansett som grunnlaget de man skulle etablere normene for biologisk korrekte tester senere. I mellomtiden førte praksisen med å måle serumjod, og likestille det med "tyroksin, skjoldbruskkjertelhormonet" til praksisen med å undersøke kun jodinnholdet i det antatte kjertelmaterialet som ble solgt som skjoldkjertelekstrakt USP. Dette førte til at de erstattet materialer i medisinen. Feks tørket skjoldbruskkjertelekstrakt ble erstattet med jodert kasein i produktene som ble solgt som "skjoldbruskkjertel USP". Amerikanske FDA nektet å iverksette tiltak, fordi de mente at et materiales jodinnhold var nok til å anse det som "skjoldbruskkjertel USP." I denne kulturen av misforståelser og misrepresentasjoner, førte den feilaktige ideen om hypotyreoses lave forekomst i befolkningen til aksept av farlig høy TSH-aktivitet som "normal". Akkurat som overdreven FSH (follikkelstimulerende hormon) har vist seg å ha en rolle i eggstokkreft, vil overdreven stimulering fra TSH gi uorganisering i skjoldbruskkjertelen. III. Tester og "frie hormonhypotesen" Etter at radioaktivt jod ble tilgjengelig, ville mange leger gi en dose og deretter skanne kroppen med en geigerteller for å se om den ble konsentrert i skjoldbruskkjertelen. Hvis en person hadde spist jodrik mat (og jod ble brukt i brød som konserveringsmiddel og var tilstede i andre matvarer som en utilsiktet forurensning), ville de allerede være overmettet med jod og kjertelen ville ikke klare å konsentrere jodet inne i kjertelen. Testen kunne finne noen typer metastatisk kreft i skjoldbruskkjertelen, men den ble vanligvis ikke brukt til det formålet. En annen dyr og underholdende test har vært thyrotropin release hormone (TRH) testen, for å se om hypofysen reagerer ved å øke TSH-produksjonen. En studie konkluderte med at "TRH-test gir mange misvisende resultater og har et forhøyet kostnad/nytte-forhold sammenlignet med den karakteristiske kombinasjonen av lav tyroksinemi og ikke-forhøyet TSH." (Bakiri, Ann. Endocr (Paris) 1999) Men til tross for det teknologiske dramaet, kostnadene og faren (Dokmetas, et al., J Endocrinol Invest 1999 Oct; 22(9): 698-700) av denne testen ville komme til å gjøre den fortsatt populær i lang tid. Hvis den spesielle verdien av testen er å diagnostisere en hypofyseabnormitet, virker det intuitivt åpenbart at overstimulering av hypofysen kanskje ikke er en god idé (det kan f.eks. føre til at en svulst vokser). Ellers, kan det være informativt å se på mengden tyroksin og TSH i blodet. Unntaket fra "regelen" angående referanseverdiene for tyroksin og TSH har dannet grunnlaget for noen teorier om "genetikken til skjoldbruskkjertelresistens", men andre har påpekt at unormale tall for T4, T3, TSH kan forklares på flere ulike måter. Den faktiske mengden av T3, det aktive skjoldbruskkjertelhormonet, i blodet kan måles med rimelig nøyaktighet (ved hjelp av radioimmunoassay, RIA), og denne enkelttesten samsvarer bedre med stoffskiftet og andre meningsfulle biologiske responser enn andre standardtester gjør. Men likevel er dette bare en statistisk korrespondanse, og det indikerer ikke at et bestemt tall er riktig for en bestemt person. Noen ganger brukes en test kalt RT3U, eller "resin T3 uptake", sammen med en måling av tyroksin. En viss mengde radioaktivt T3 tilsettes en prøve av serum, og deretter eksponeres et absorberende materiale for blandingen. Mengden radioaktivitet som fester seg til harpiksen kalles T3-opptaket. Laboratorierapporten gir da et tall kalt T7, eller fri tyroksinindeks. Jo nærmere denne prosedyren undersøkes, jo dummere ser den ut, og den ser ganske dum ut.. Tanken om at den tilsatte radioaktive T3 som fester seg til et stykke harpiks vil tilsvare "fritt tyroksin," er i seg selv merkelig, men det virkelig interessante er, hva mener de med "fritt tyroksin"? Tyroksin er et ganske hydrofobt (uløselig i vann) stoff, som vil assosieres med proteiner, celler og lipoproteiner i blodet, i stedet for å løses opp i vann. Selv om Merck Index beskriver det som "uløselig i vann", inneholder det noen polare grupper som under de rette (industrielle eller laboratoriemessige) forhold kan gjøre det litt vannløselig. Dette gjør det litt forskjellig fra progesteron, som er enkelt og greit uløselig i vann, selv om begrepet "fritt hormon" ofte brukes på progesteron, som det fra skjoldbruskkjertelen. Når det gjelder progesteron, kan begrepet "fritt progesteron" spores til eksperimenter der serum som inneholder progesteron (bundet til proteiner) separeres med en (dialyse) membran fra en løsning av lignende proteiner som ikke inneholder progesteron. Progesteron "oppløses i" stoffet i membranen, og serumproteinene, som også har en tendens til å assosieres med membranen, er så store at de ikke passerer gjennom den. På den andre siden tar proteiner som kommer i kontakt med membranen opp noe progesteron. Progesteronet som går gjennom kalles "fritt progesteron", men fra det eksperimentet, som ikke gir noe informasjon om arten av interaksjonene mellom progesteron og dialysemembranen, eller om dets interaksjoner med proteinene, eller proteinenes interaksjoner med membranen så vil Ingenting avsløres om årsakene til overføring eller utveksling av en viss mengde progesteron. Likevel brukes den typen eksperimenter for å tolke hva som skjer i kroppen, hvor det ikke er noe som tilsvarer forsøksoppsettet, bortsett fra at noe progesteron er assosiert med noe protein. Ideen om at det "frie hormonet" er den aktive formen har blitt testet i noen få situasjoner, og når det gjelder skjoldbruskkjertelhormonet, er det åpenbart ikke riktig for hjernen og visse andre organer. Det proteinbundne hormonet er i disse tilfellene den aktive formen; assosiasjonene mellom det "frie hormonet" og de biologiske prosessene og sykdommene vil være fullstendig falske, hvis de ignorerer de aktive formene av hormonet til fordel for de mindre aktive formene. Konklusjonene vil være uriktige, slik de er når T4 måles, og T3 ignoreres. Skjoldkjertelavhengige prosesser vil se ut til å være uavhengige av nivået av skjoldbruskkjertelhormon; hypotyreose kan være "caller" hypertyreose. Selv om progesteron er mer fettløselig enn kortisol og skjoldbruskkjertelhormonene, illustrerer oppførselen til progesteron i blodet noen av problemene som må vurderes for å tolke thyreoideafysiologien. Når røde blodlegemer brytes opp, viser det seg at de inneholder progesteron i omtrent dobbelt så høy konsentrasjon som serumet. I serumet bæres sannsynligvis 40 til 80 % av progesteronet på albumin. (Albumin leverer enkelt sin progesteronbelastning inn til vev.) Progesteron, som kolesterol, kan fraktes videre/i lipoproteinene, i moderate mengder. Dette etterlater en veldig liten brøkdel som kan bindes til "steroidbindende globulin." Alle som har forsøkt å løse opp progesteron i ulike løsemidler og blandinger vet at det bare trengs en liten mengde vann i et løsningsmiddel for å få progesteron til å utfelles fra løsningen som krystaller; dens løselighet i vann er i hovedsak null. "Fri" progesteron ser ut til å bety progesteron som ikke er festet til proteiner eller oppløst i røde blodceller eller lipoproteiner, og dette vil være null. Testene som hevder å måle fritt progesteron måler noe, men ikke progesteronet i den vannholdige fraksjonen av serumet. Skjoldbruskkjertelhormonene assosieres med tre typer enkle proteiner i serumet: Transthyretin (prealbumin), skjoldbruskbindende globulin og albumin. En svært betydelig mengde er også assosiert med forskjellige serumlipoproteiner, inkludert HDL, LDL og VLDL (lipoproteiner med svært lav tetthet). En svært stor del av stoffskiftehormonet i blodet er assosiert med de røde blodcellene. Da røde blodlegemer ble inkubert i et medium som inneholdt serumalbumin, med cellene i omtrent konsentrasjonen funnet i blodet, beholdt de T3 i en konsentrasjon som var 13,5 ganger høyere enn konsentrasjonen til mediet. I en større mengde medium var konsentrasjonen av T3 50 ganger høyere enn mediets. Når laboratorier kun måler hormonene i serumet, har de allerede kastet ut omtrent 95 % av skjoldbruskkjertelhormonet som blodet inneholdt. T3 ble funnet å være sterkt assosiert med cellenes cytoplasmatiske proteiner, men å bevege seg raskt mellom proteinene inne i cellene og andre proteiner utenfor cellene. Når folk snakker om hormoner som reiser «på» de røde blodcellene, i stedet for «i» dem, er det en innrømmelse av læren om den ugjennomtrengelige membranbarrieren. Mye mer T3 bundet til albumin tas opp av leveren enn den lille mengden identifisert in vitro som fritt T3 (Terasaki, et al., 1987). Den spesifikke bindingen av T3 til albumin endrer proteinets elektriske egenskaper, og endrer måten albuminet interagerer med celler og andre proteiner på. (Albumin blir elektrisk mer positivt når det binder hormonet; dette vil få albuminet til å gå lettere inn i cellene. Ved å gi fra seg T3 til cellen, vil det bli mer negativt, noe som gjør at det har en tendens til å forlate cellen.) Denne aktive rollen til albumin ved å hjelpe cellene med å ta opp T3, kan det forklare dets økte opptak av de røde blodcellene når det var færre celler i forhold til albuminmediet. Dette kan også forklare den gunstige prognosen forbundet med høyere nivåer av serumalbumin ved ulike sykdommer. Når T3 er festet kjemisk (kovalent, permanent) til utsiden av røde blodceller, og tilsynelatende forhindrer dets inntreden i andre celler, produserer tilstedeværelsen av disse røde cellene reaksjoner i andre celler som er de samme som noen av de som produseres av det antatte "frie hormonet." Hvis T3 knyttet til hele celler kan utøve sin hormonelle virkning, hvorfor skal vi tenke at hormonet bundet til proteiner ikke er i stand til å påvirke cellene? Ideen med å måle det "frie hormonet" er at det angivelig representerer det biologisk aktive hormonet, men det er faktisk lettere å måle de biologiske effektene enn det er å måle denne hypotetiske enheten. IV. Hendelser i vevet Foruten effektene av kommersielt bedrag, har forvirring om skjoldbruskkjertelen oppstått fra noen biologiske klisjeer. Ideen om en "barrieremembran" rundt celler er en antagelse som har påvirket de fleste som studerer cellefysiologi, og effektene kan sees i nesten alle de tusenvis av publikasjonene om funksjonene til skjoldbruskkjertelhormoner. Ifølge denne ideen har folk beskrevet en celle som ligner en dråpe av en vannaktig løsning, innelukket i en oljeaktig pose som skiller den indre løsningen fra den ytre vannholdige løsningen. Klisjeen opprettholdes bare ved å neglisjere det faktum at proteiner har stor tilhørighet til fett, og fett til proteiner; selv løselige proteiner, som serumalbumin, har ofte et indre som er ekstremt fettelskende. Siden de strukturelle proteinene som utgjør rammeverket til en celle ikke er "oppløst i vann" (de pleide å bli kalt "de uløselige proteinene"), er den lipofile fasen ikke begrenset til en ultramikroskopisk tynn overflate, men utgjør faktisk hoveddelen av cellen. Molekylærgenetikere liker å knytte vitenskapen sin til et eksperiment fra 1944 som ble utført av Avery., et al. Averys gruppe visste om et tidligere eksperiment, som hadde vist at når døde bakterier ble lagt med levende bakterier, dukket egenskapene til de døde bakteriene opp i de levende bakteriene. Averys gruppe ekstraherte DNA fra de døde bakteriene, og viste at å legge det ved levende bakterier, overføres egenskapene fra de døde organismene til de levende. På 1930- og 1940-tallet var bevegelsen av enorme molekyler som proteiner og nukleinsyrer inn i celler og ut av celler ikke en stor sak; folk observerte at det skjedde, og skrev om det. Men på 1940-tallet begynte ideen om barrieremembranen å få tyngde, og på 1960-tallet var ingenting i stand til å komme inn i cellene uten autorisasjon. For øyeblikket tviler jeg på at noen molekylærgenetiker ville drømme om å gjøre en gentransplantasjon uten en "vektor" for å bære den over membranbarrieren. Siden store molekyler er ment å bli ekskludert fra celler, er det bare det "frie hormonet" som kan finne sin spesifikke inngangsport inn i cellen, der en annen klisje sier at den må reise inn i kjernen, for å reagere med et bestemt sted for å aktivere spesifikke gener som dens virkninger vil bli uttrykt gjennom. Jeg kjenner ikke til noe hormon som virker på den måten. Skjoldbruskkjertelhormon, progesteron og østrogen har mange umiddelbare effekter som endrer cellens funksjoner lenge før gener kunne aktiveres. Transthyretin, som bærer skjoldbruskkjertelhormonet, går inn i cellens mitokondrier og kjerne (Azimova, et al., 1984, 1985). I kjernen forårsaker det umiddelbart generaliserte endringer i strukturen til kromosomene, som om det forbereder cellen på store adaptive endringer. Respirasjonsaktivering er umiddelbar i mitokondriene, men etter hvert som respirasjonen stimuleres, reagerer alt i cellen, inkludert genene som støtter respiratorisk metabolisme. Når membranfolket snakker om at store molekyler kommer inn i celler, bruker de begreper som "endocytose" og "translokaser", som inkorporerer antagelsen om barrieren. Men folk som faktisk undersøker problemet, finner generelt at "diffusjon", "kodiffusjon" og absorpsjon beskriver situasjonen på en adekvat måte (f.eks. B.A. Luxon, 1997; McLeese og Eales, 1996). "Aktiv transport" og "membranpumper" er ideer som virker nødvendige for folk som ikke har studert de komplekse kreftene som virker ved fasegrenser, for eksempel grensen mellom en celle og dens miljø. V. Terapi For mange år siden ble det rapportert at Armour Thyroid, U.S.P., frigjorde T3 og T4 når de ble fordøyd, i forholdet 1:3, og at folk som brukte det hadde mye høyere forhold mellom T3 og T4 i serumet enn folk som bare tok tyroksin. Argumentet som ble fremsatt var at tyroksin var overlegen Thyroid U.S.P., uten å forklare betydningen av det faktum at friske mennesker som ikke tok noe skjoldbruskkjerteltilskudd hadde høyere T3:T4-forhold enn de som tok tyroksin, eller at vår egen skjoldbruskkjertel frigjør et høyt forhold av T3 til T4. Det faktum at T3 brukes raskere enn T4, og fjerner det fra blodet raskere enn det kommer inn fra selve skjoldbruskkjertelen, har ikke blitt diskutert i journalene, muligens fordi det ville støtte oppfatningen om at en naturlig kjertelbalanse var mer hensiktsmessig å supplere enn ren tyroksin. Serumets høye forhold mellom T4 og T3 er et ynkelig dårlig argument for å rettferdiggjøre bruken av tyroksin i stedet for et produkt som ligner andelen av disse stoffene som skilles ut av en sunn skjoldbruskkjertel, eller opprettholdes inne i cellene. For rundt 30 år siden, da mange mennesker fortsatt tenkte på tyroksin som "skjoldkjertelhormonet", var det noen som kom med argumentet at "skjoldkjertelhormonet" utelukkende må fungere som en aktivator av gener, siden de fleste organskivene han testet, ikke økte oksygenforbruket da det ble tilsatt. Faktisk senket tilsetningen av tyroksin til hjerneskiver pusten deres med 6 % under eksperimentet. Siden det meste av T3 produseres fra T4 i leveren, ikke i hjernen, tror jeg eksperimentet hadde stor betydning, til tross for forfatterens uvitende tolkning. Et overskudd av tyroksin i et vev som ikke konverterer det raskt til T3, har en antithyroidvirkning. (Se Goumaz, et al, 1987.) Dette skjer hos mange kvinner som får tyroksin; i takt med at dosen økes, blir symptomene verre. Hjernen konsentrerer T3 fra serumet, og kan ha en konsentrasjon 6 ganger høyere enn serumet (Goumaz, et al., 1987), og den kan oppnå en høyere konsentrasjon av T3 enn T4. Den tar opp og konsentrerer T3, mens den har en tendens til å utvise T4. Revers T3 (rT3) har ikke lik evne til å trenge inn i hjernen, men økt T4 kan føre til at det produseres i hjernen. Disse observasjonene antyder for meg at blodets T3:T4-forhold ville være veldig "hjernegunstig" hvis det nærmet seg forholdet som dannes i skjoldbruskkjertelen og skilles ut i blodet. Selv om de fleste syntetiske kombinasjonsprodukter for skjoldbruskkjertelen nå bruker et forhold på fire T4 til én T3, føler mange at hukommelsen og tenkningen deres er klarere når de tar et forhold på omtrent tre til én. Mer aktiv metabolisme holder sannsynligvis blodforholdet mellom T3 og T4 relativt høyt, med leveren som konsumerer T4 med omtrent samme hastighet som T3 brukes. Siden T3 har kort halveringstid, bør det tas ofte. Hvis leveren ikke produserer en merkbar mengde T3, er det vanligvis nyttig å ta noen mikrogram per time. Siden det gjenoppretter respirasjonen og metabolsk effektivitet veldig raskt, er det vanligvis ikke nødvendig å ta det hver time eller hver andre time, men inntil normal temperatur og puls er oppnådd og stabilisert, er det noen ganger nødvendig å ta det fire eller flere ganger i løpet av dagen. T4 virker ved å bli konvertert til T3, så det har en tendens til å samle seg i kroppen, og ved en gitt dose når det vanligvis en jevn konsentrasjon etter omtrent to uker. En effektiv måte å bruke hormontilskudd på er å ta en kombinasjon av T4-T3-dose, f.eks. 40 mcg T4 og 10 mcg T3 en gang daglig, og å bruke noen få mcg T3 på andre tidspunkter på dagen. Ved å lage et 14-dagers diagram over puls og temperatur kan du se om dosen gir ønsket respons. Hvis tallene ikke øker i det hele tatt etter noen dager, kan dosen økes inntil en gradvis daglig økning kan sees, og beveger seg mot målet med et nivå på omtrent 1/14 per dag. VI. Diagnose I mangel av kommersielle teknikker som reflekterer skjoldbruskkjertelens fysiologi realistisk, er det ikke noe gyldig alternativ til diagnosering basert på kjente fysiologiske indikatorer for hypotyreose og hypertyreose. Unnlatelse av å behandle syke mennesker på grunn av en eller annen blodprøve som indikerer "normal skjoldbruskkjertelfunksjon", eller ødeleggelse av pasientens friske skjoldbruskkjertler fordi en av testene indikerer hypertyreose, er ikke akseptabelt bare fordi det er den profesjonelle standarden, og håndheves av ignorante statlige lisensstyrer. Mot slutten av det tjuende århundre har det vært en betydelig diskusjon om «evidensbasert medisin». God dømmekraft krever god informasjon, men det er krefter som vil overstyre individuelle vurderinger av hvorvidt publisert informasjon er anvendelig for enkelte pasienter. I en atmosfære som godkjenner forskrivning av østrogen eller insulin uten bevis på østrogenmangel eller insulinmangel, men som straffer behandlere som foreskriver skjoldkjertelhormon for å korrigere symptomer, er det publiserte "beviset" nødvendigvis sterkt partisk. I denne sammenhengen blir "metaanalyse" et verktøy for autoritarisme, og erstatter bruken av dømmekraft med feil bruk av statistisk analyse. Med mindre noen kan påvise den vitenskapelige ugyldigheten til metodene som ble brukt for å diagnostisere hypotyreose frem til 1945, utgjør de det beste beviset for å evaluere hypotyreose, fordi alle blodprøvene som har blitt brukt siden 1950 har vist seg å være i beste fall veldig grove og konseptuelt upassende metoder. Thomas H. McGavacks bok fra 1951, The Thyroid, var representativ for den tidligere tilnærmingen til studiet av thyreoideafysiologi. Kjennskap til de ulike effektene av unormal skjoldbruskkjertelfunksjon under ulike forhold, i ulike aldre, og effektene av kjønn, var standardemner i medisinsk utdanning, men forsvant ved slutten av århundret. Leddgikt, uregelmessig vekst, fedme, en rekke unormaliteter i hår og hud, karotenemi, amenoré, tendens til spontanabort, infertilitet hos menn og kvinner, søvnløshet eller somnolens, emfysem, ulike hjertesykdommer, psykose, demens, dårlig hukommelse, angst, kalde ekstremiteter, anemi og mange andre problemer var kjente grunner til å mistenke hypotyreose. Hvis legen ikke hadde en enhet for å måle oksygenforbruk, kunne estimert kaloriinntak gi støttende bevis. Akilles-senerefleksen var en annen enkel objektiv måling med en veldig sterk korrelasjon til den basale metabolske hastigheten. Elektrisk motstand i huden eller impedans for hele kroppen var ikke allment akseptert, selv om den hadde betydelig vitenskapelig gyldighet. En terapeutisk utprøving var den siste testen av gyldigheten til diagnosen: Hvis pasientens symptomer forsvant ettersom temperaturen og pulsen og matinntaket ble normalisert, ble den diagnostiske hypotesen bekreftet. Det var vanlig å starte behandlingen med ett eller to grain av skjoldkjertelekstrakt, og å justere dosen i henhold til pasientens respons. Uansett hvilken objektiv indikator som ble brukt, enten det var basal metabolsk hastighet, serumkolesterol, kjernetemperatur, eller refleksavslapningshastighet, ville et enkelt diagram demonstrere bedringen mot normal helse. http://raypeat.com/articles/articles/thyroid.shtml REFERANSER McGavack, Thomas Hodge.: The thyroid,: St. Louis, Mosby, 1951. 646 p. ill.Several chapters contributed by various authors. Call Numbers WK200 M145t 1951 (Rare Book). Endocrinology 1979 Sep; 105(3): 605-12. Carrier-mediated transport of thyroid hormones through the rat blood-brain barrier: primary role of albumin-bound hormone. Pardridge WM. Endocrinology 1987 Apr;120(4):1590-6. Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger A.G. J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis. Pardridge WM, Landaw EM. Previous studies have shown that the fraction of hormone or drug that is plasma protein bound is readily available for transport through the brain endothelial wall, i.e., the blood-brain barrier (BBB). To test whether these observations are reconcilable with the free-hormone hypothesis, a tracer-kinetic model is used Endocrinology 113(1), 391-8, 1983, Stimulation of sugar transport in cultured heart cells by triiodothyronine (T2) covalently bound to red blood cells and by T3 in the presence of serum, Dickstein Y, Schwartz H, Gross J, Gordon A. Endocrinology 1987 Sep; 121(3): 1185-91. Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier- and plasma protein-mediated transport. Terasaki T, Pardridge WM. J. Neurophysiol 1994 Jul;72(1):380-91. Film autoradiography identifies unique features of [125I]3,3'5'-(reverse) triiodothyronine transport from blood to brain. Cheng LY, Outterbridge LV, Covatta ND, Martens DA, Gordon JT, Dratman MB Brain Res 1991 Jul 19;554(1-2):229-36. Transport of iodothyronines from bloodstream to brain: contributions by blood:brain and choroid plexus:cerebrospinal fluid barriers. Dratman MB, Crutchfield FL, Schoenhoff MB.. Mech Ageing Dev 1990 Mar15;52(2-3):141-7. Blood-brain transport of triiodothyronine is reduced in aged rats. Mooradian AD Geriatrics Section, Tucson VA Medical Center, AZ. Endocrinology 1987 Sep;121(3):1185-91. Stereospecificity of triiodothyronine transport into brain, liver, and salivary gland: role of carrier- and plasma protein-mediated transport. Terasaki T, Pardridge WM. J Clin Invest 1984 Sep;74(3):745-52. Tracer kinetic model of blood-brain barrier transport of plasma protein-bound ligands. Empiric testing of the free hormone hypothesis. Pardridge WM, Landaw EM. 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D Novitzky, H Fontanet, M Snyder, N Coblio, D Smith, V Parsonnet, Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery, Cardiology, 1996, Vol 87, Iss 6, pp 509-515. Biochim Biophys Acta 1997. Jan 16;1318(1-2):173-83 Regulation of the energy coupling in mitochondria by some steroid and thyroid hormones. Starkov AA, Simonyan RA, Dedukhova VI, Mansurova SE, Palamarchuk LA, Skulachev VP Thyroid 1996 Oct;6(5):531-6. Novel actions of thyroid hormone: the role of triiodothyronine in cardiac transplantation. Novitzky D. Rev Med Chil 1996 Oct;124(10):1248-50. [Severe cardiac failure as complication of primary hypothyroidism]. Novik V, Cardenas IE, Gonzalez R, Pena M, Lopez Moreno JM. Cardiology 1996 Nov-Dec;87(6):509-15. Impact of triiodothyronine on the survival of high-risk patients undergoing open heart surgery. Novitzky D, Fontanet H, Snyder M, Coblio N, Smith D, Parsonnet V Curr Opin Cardiol 1996 Nov;11(6):603-9. The use of thyroid hormone in cardiac surgery. Dyke C N Koibuchi, S Matsuzaki, K Ichimura, H Ohtake, S Yamaoka. Ontogenic changes in the expression of cytochrome c oxidase subunit I gene in the cerebellar cortex of the perinatal hypothyroid rat. Endocrinology, 1996, Vol 137, Iss 11, pp 5096-5108. Biokhimiia 1984 Aug;49(8):1350-6. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. [Article in Russian] Azimova ShS, Umarova GD, Petrova OS, Tukhtaev KR, Abdukarimov A. The in vivo translocation of thyroxine-binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. Am J Physiol 1997 Sep;273(3 Pt 1):C859-67. Cytoplasmic codiffusion of fatty acids is not specific for fatty acid binding protein. Luxon BA, Milliano MT [The nature of thyroid hormone receptors. Intracellular functions of thyroxine-binding prealbumin] Azimova ShS; Normatov K; Umarova GD; Kalontarov AI; Makhmudova AA, Biokhimiia 1985 Nov;50(11):1926-32. The effect of tyroxin-binding prealbumin (TBPA) of blood serum on the template activity of chromatin was studied. It was found that the values of binding constants of TBPA for T3 and T4 are 2 X 10(-11) M and 5 X 10(-10) M, respectively. The receptors isolated from 0.4 M KCl extract of chromatin and mitochondria as well as hormone-bound TBPA cause similar effects on the template activity of chromatin. Based on experimental results and the previously published comparative data on the structure of TBPA, nuclear, cytoplasmic and mitochondrial receptors of thyroid hormones as well as on translocation across the plasma membrane and intracellular transport of TBPA, a conclusion was drawn, which suggested that TBPA is the "core" of the true thyroid hormone receptor. It was shown that T3-bound TBPA caused histone H1-dependent conformational changes in chromatin. Based on the studies with the interaction of the TBPA-T3 complex with spin-labeled chromatin, a scheme of functioning of the thyroid hormone nuclear receptor was proposed. [The nature of thyroid hormone receptors. Thyroxine- and triiodothyronine-binding proteins of mitochondria] Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Sep;49(9):1478-85. T4- and T3-binding proteins of rat liver were studied. It was found that the external mitochondrial membranes and matrix contain a protein whose electrophoretic mobility is similar to that of thyroxine-binding blood serum prealbumin (TBPA) and which binds either T4 or T3. This protein is precipitated by monospecific antibodies against TBPA. The internal mitochondrial membrane has two proteins able to bind thyroid hormones, one of which is localized in the cathode part of the gel and binds only T3, while the second one capable of binding T4 rather than T3 and possessing the electrophoretic mobility similar to that of TBPA. Radioimmunoprecipitation with monospecific antibodies against TBPA revealed that this protein also the antigenic determinants common with those of TBPA. The in vivo translocation of 125I-TBPA into submitochondrial fractions was studied. The analysis of densitograms of submitochondrial protein fraction showed that both TBPA and hormones are localized in the same protein fractions. Electron microscopic autoradiography demonstrated that 125I-TBPA enters the cytoplasm through the external membrane and is localized on the internal mitochondrial membrane and matrix. [The nature of thyroid hormone receptors. Translocation of thyroid hormones through plasma membranes]. Azimova ShS; Umarova GD; Petrova OS; Tukhtaev KR; Abdukarimov A. Biokhimiia 1984 Aug;49(8):1350-6.. The in vivo translocation of thyroxine- binding blood serum prealbumin (TBPA) was studied. It was found that the TBPA-hormone complex penetrates-through the plasma membrane into the cytoplasm of target cells. Electron microscopic autoradiography revealed that blood serum TBPA is localized in ribosomes of target cells as well as in mitochondria, lipid droplets and Golgi complex. Negligible amounts of the translocated TBPA is localized in lysosomes of the cells insensitive to thyroid hormones (spleen macrophages). Study of T4- and T3-binding proteins from rat liver cytoplasm demonstrated that one of them has the antigenic determinants common with those of TBPA. It was shown autoimmunoradiographically that the structure of TBPA is not altered during its translocation. Endocrinology 1987 Apr;120(4):1590-6 Brain cortex reverse triiodothyronine (rT3) and triiodothyronine concentrations under steady state infusions of thyroxine and rT3. Goumaz MO, Kaiser CA, Burger AG. Gen Comp Endocrinol 1996 Aug;103(2):200-8 Characteristics of the uptake of 3,5,3'-triiodo-L-thyronine and L-thyroxine into red blood cells of rainbow trout (Oncorhynchus mykiss). McLeese JM, Eales JG. Prog Neuropsychopharmacol Biol Psychiatry 1998 Feb;22(2):293-310. Increase in red blood cell triiodothyronine uptake in untreated unipolar major depressed patients compared to healthy volunteers. Moreau X, Azorin JM, Maurel M, Jeanningros R. Biochem J 1982 Oct 15;208(1):27-34. Evidence that the uptake of tri-iodo-L-thyronine by human erythrocytes is carrier-mediated but not energy-dependent. Docter R, Krenning EP, Bos G, Fekkes DF, Hennemann G. J Clin Endocrinol Metab 1990 Dec;71(6):1589-95. Transport of thyroid hormones by human erythrocytes: kinetic characterization in adults and newborns. Osty J, Valensi P, Samson M, Francon J, Blondeau JP. J Endocrinol Invest 1999 Apr;22(4):257-61. Kinetics of red blood cell T3 uptake in hypothyroidism with or without hormonal replacement, in the rat. Moreau X, Lejeune PJ, Jeanningros R. © Ray Peat 2006. www.RayPeat.com

Skrevet av Dr. John C. Lowe på hans nettside Thyroid Science, med spørsmål og svar. Originalspråk: Engelsk 20. juni, 2010 Spørsmål: Jeg er allmennlege i Storbritannia. Mange av pasientene mine har fortalt meg at de ble friske etter hypothyroidsymptomene sine etter at de fant en privat lege som behandlet dem med tyroksin til tross for deres normale TSH-nivåer. Disse pasientene hadde blitt nektet tyroksinbehandling av leger innen nasjonal helsesektor på grunn av deres normale TSH-nivåer. Så mange pasienter har fortalt meg dette, at jeg har utviklet et forbehold om å utelukke hypotyreose og behovet for tyroksinbehandling basert på en normal TSH-test. Mange flere av mine pasienter med normale TSH-nivåer ber meg skrive ut tyroksin eller Armour Thyroid. Jeg nøler med å etterkomme dette på grunn av Royal College of Physicians' uttalelse om uønskede effekter av unødvendig thyroidhormonbehandling. Kan jeg få høre ditt synspunkt omkring potensialet for bivirkninger av tyroksinbehandling i tilfeller hvor pasienten egentlig ikke trenger det? Dr. Lowe: Jeg er kjent med uttalelsen du refererer til fra Royal College of Physicians. Spesifikt er det: ". . . noen pasienter er upassende diagnostisert som hypothyroide (ofte utenfor nasjonal helsesektor) og begynner på tyroksin eller andre skjoldbruskhormoner som ikke bare vil forårsake dem mulig skade, men ...." Som ved mange andre utsagn fra Royal College of Physicians, når det snakkes om den generelle befolkningen, er dette åpenbart feilaktig. Med mindre du er en geriatrisk spesialist hvis pasienter er blant de mest skjøre av mennesker, selv om de ikke trenger supplerende skjoldbruskkjertelhormon, er en utprøving av skjoldbruskhormonbehandling ufarlig. Hvis hormonet ikke hjelper dem, kan du trappe ned medisinen og stoppe behandlingen helt. Ingen skade skjedd! Beviser for dette er i arkivet til FDA-veiledede studier av styrken og stabiliteten til T4. For å teste T4 for styrke og stabilitet, har forskere – ved hjelp av FDA-testveiledning! – tradisjonelt brukt frivillige som var «euthyreoide», noe som selvfølgelig betyr at forsøkspersonene hadde normale testresultater når det gjelder skjoldbruskkjertelen. Videre har testveiledning fra FDA tillatt forskere å bruke euthyroide frivillige for å teste høyere enn fysiologiske (suprafysiologiske) doser av T4. [1, s.109] IJeg spør Royal College of Physicians: Hvis det var sannsynlig at dette ville skade euthyroide frivillige, hvorfor ville FDA-testveiledning tillatt at forskere brukte dem til utprøvingen i det hele tatt? Og hvorfor skulle institusjonelle styrer godkjenne studiene som ikke potensielt skadelige for de frivillige? Svaret er selvfølgelig enkelt: En utprøving av skjoldbruskkjertelhormonbehandling - selv for personer med helt normal skjoldbruskkjertelfunksjon - er ufarlig, selv når de bruker suprafysiologiske doser. Først nylig har forskere antydet at i stedet for å teste euthyreoide frivillige, ville de gjøre best i å bruke tyreoidektomiserte pasienter. Men forskernes begrunnelse for dette forslaget har ingenting å gjøre med noen skade som noen gang er gjort på euthyroide frivillige i studiene. Testingen har ikke skadet de euthyroide frivillige, og heller ikke en utprøving av tyreoideahormonbehandling vil skade praktisk talt noen av de euthyroide pasientene dine bortsett fra muligens de aller mest skjøre av dem. Men, en kopp kaffe vil like sannsynlig skade disse skjøre menneskene. Jeg forstår det bare ikke: Hvordan kan Royal College of Physicians (som med denne spesifikke saken) og British Thyroid Association komme med vitenskapelig falske utsagn og stå ved dem i møte med bevis på at de er falske, men allikevel mottar de ingen irettesettelser fra regulerende myndigheter? For meg er deres falske utsagn en krenkelse av den edle vitenskapstradisjonen, og organisasjonene som holder fast ved sine falske utsagn i møte med tilbakevisende bevis reduserer utsagnene til eksempler på pseudovitenskap. I alle fall håper jeg dette svaret er nyttig for deg for å gi pasientene dine ufarlige utprøvinger av skjoldbruskhormonbehandling, enten de virkelig trenger det eller ikke. Referanser 1. Royal College of Physicians. The diagnosis and management of primary hypothyroidism. 2008. 2. Eisenberg, M. and DiStefano, III, J.J.: TSH-Based Protocol, Tablet Instability, and Absorption Effects on L-T4 Bioequivalence. Thyroid, 19(2):103-110, 2009. 12. juni 2010 Spørsmål: Jeg har en hypoteserapport som jeg vurderer å sende inn til Thyroid Science. Jeg er imidlertid litt nølende, fordi det kan være fordeler med å publisere i store medisinske tidsskrifter. Selvfølgelig kan jeg ha vanskeligere for å få rapporten min akseptert pga konkurranse. Hva er dine tanker for nye personer når det gjelder å sende inn artikler til tidsskrifter? Kan jeg sende inn oppgaven min både til Thyroid Science og et annet tidsskrift og deretter benytte hvilken som helst av den som måtte godta forslaget mitt? Dr. Lowe: Mange har stilt oss det samme spørsmålet. Selvfølgelig vil vi gjerne ha en sjanse til å publisere rapporten ditt hvis våre anmeldere mener det har god nytte innen tyreoidologi. Men hvis rapporten ditt kan bidra til å endre det nåværende "T4-erstatningsparadigmet" for hypotyreose, bryr vi oss egentlig ikke om hvilket tidsskrift som først publiserer det, så lenge du får det publisert. For noen kan denne politikken virke selvsaboterende for Thyroid Science, men det er den egentlig ikke. Hvis vi føler at en artikkel publisert andre steder er viktig nok, ber vi forfatteren(e) om å skrive et sammendrag av oppgaven for tidsskriftet vårt, muligens ytterligere spesifisere rapporten og gi enda flere støttende beviser. Og hvis forfatteren ikke vil samarbeide omkring dette, kan vi komponere en artikkel basert på forfatteren(e) som uansett bringer viktig informasjon til våre lesere. Når du bestemmer deg for hvor du skal sende inn rapporten, kan du huske på noen punkter jeg skrev til en annen potensiell forfatter i morges. Det jeg skrev til ham er i hovedsak følgende: For lenge siden, da jeg ble utdannet i forskningspsykologi (jeg tror Galileo satt to rader foran meg), tok jeg kurs som omhandlet etikk i vitenskapelig atferd. Vi ble lært at det er uetisk å publisere nøyaktig samme artikkel i mer enn ett tidsskrift, selv om det har gått flere år siden den første publiseringen. Den politikken er eldgammel, men den gjelder fortsatt. På grunn av dette bør du bare sende inn rapporten til én journal om gangen. Hvis den første journalen avviser rapporten din, så, og først da, send den inn til den neste. Hvis du ønsker å spre hypotesen din bredere enn én journal tillater, kan du enkelt gjøre det. Først publiserer du rapporten i ett tidsskrift, og så skriver du så mange andre artikler du vil for andre tidsskrifter. Dette er helt etisk så lenge de andre versjonene av papiret ditt faktisk er andre versjoner; det vil si at i påfølgende artikler bør du uttrykke hypotesen din nøyaktig slik den opprinnelig ble publisert, men i andre termer. Å uttrykke de samme tankene i forskjellige termer er etisk. Etter mitt syn, hvis du føler at hypotesen din kan føre til lindring av lidelse for mennesker, har du et humanitært ansvar for å publisere den så mange ganger som nødvendig for å oppnå det endelige målet. Hvis du kan få rapporten din godtatt av en stor tradisjonell trykket avis, vil du få noen viktige fordeler. For eksempel vil du sannsynligvis ha mer prestisje i øynene til den typiske praktiserende konvensjonelle klinikeren, og rapporten din vil bli inkludert i de tradisjonelle store indekseringssystemene, som Medline. På den annen side kan det trykkede tidsskriftet mislykkes i å publisere papiret ditt i en elektronisk versjon av tidsskriftet med åpen tilgang. I så fall vil sannsynligvis bare de som abonnerer på den trykkede versjonen av tidsskriftet lese hele rapporten din. Etter hvert som tiden går, vil den eneste delen av rapporten som de fleste interesserte vil få tilgang til, være sammendraget som er online. De kan få tilgang til abstraktet ditt gjennom de fleste søkemotorer, for eksempel Google og Yahoo. Ellers, hvis noen er interessert nok i å få en kopi av hele rapporten din, vil han eller hun ha ett av to alternativer: For det første kan han eller hun kjøpe en kopi på nettet fra journalen med lukket tilgang. Dette kan være dyrt, og det kan være uoverkommelig hvis man gjør mye forskning. For det andre kan han eller hun reise til et medisinsk bibliotek, spore opp rapporten din i et innbundet bind av alle rapportene som er publisert i det tidsskriftet i løpet av året, og fotokopiere det. Dette alternativet er upraktisk for de fleste. Dette kan forklare at jeg de siste årene har sett færre og færre mennesker i medisinske biblioteker som kopierer journalartikler. En annen ulempe med tradisjonelle trykkede tidsskrifter er noe som frustrerte mange av oss som pleide å publisere i tradisjonelle trykkede tidsskrifter: «publiseringsetterslepet». Jeg vet om noen journaler som hadde et etterslep på to år. Dette betydde at da ens artikkel ble publisert, var det mer historie enn nyheter. På grunn av publiseringsforsinkelsen oppfordrer jeg deg til å snakke eller skrive til en redaktør av tidsskriftet du bestemmer deg for å sende inn til. Som om tidsskriftet i tillegg til å publisere en trykket versjon også raskt vil publisere en elektronisk versjon på nettet. En annen viktig sak er om tidsskriftet kun er tilgjengelig for abonnenter ("lukket tilgang") eller er "åpen tilgang". Åpen tilgang betyr at de fleste publikasjoner i tidsskriftet er gratis å lese uten abonnement. Stadig flere tidsskrifter med åpen tilgang publiseres, og de påvirker tradisjonelle trykte tidsskrifter. Når jeg har spurt, har medisinske bibliotekarer, som jobber der tradisjonelle trykte journaler er lagret, fortalt meg, "åpen tilgangsjournaler dreper oss." En fordel med elektronisk publisering, spesielt i tidsskrifter med åpen tilgang som Thyroid Science, er at vi praktisk talt ikke har noe etterslep. Vi publiserer artikler er raskt sammenlignet med trykte tidsskrifter. I tillegg, med tidsskrifter med åpen tilgang, kan alle i verden med tilgang til Internett finne og lese oppgaven din ved hjelp av Google, Yahoo eller de fleste andre søkemotorer. Man trenger ikke engang å bruke Medline, PubMed eller noen av de andre tradisjonelle indekseringssystemene. Faktisk tror jeg disse systemene er på grensen til å bli foreldet. De fleste søkemotorer som Google indekserer også papirene som tidligere bare ble indeksert i de tradisjonelle indekseringssystemene. I tillegg indekserer søkemotorer på Internett også publikasjoner som ikke er inkludert i PubMed. Hvis du publiserer i et annet tidsskrift for en eller annen fordel, støtter vi deg fullt ut i det. Og hvis du sender oss en avansert kopi av rapporten din, etter at det andre tidsskriftet har publisert det, kan vi be deg om å oppsummere hypotesen din og utdype den i en annen artikkel for Thyroid Science. Lykke til med å få publisert hypotesen din, uansett hvor du bestemmer deg for å sende inn rapporten. 24. november 2009 Spørsmål: Legen min ga meg laboratorieresultatene mine i går. Jeg vet hva de fleste skjoldbruskkjerteltestene er, men jeg har aldri hørt om den ene. Det er "prealbumin". Vet du hva dette er? Nivået mitt var 0,20 g/L, og referanseområdet er oppført som 0,18 til 0,39 g/L. Vet du hva dette resultatet betyr? Dr Lowe: Vi har et nyere navn for prealbumin, som er "transthyretin." Transthyretin er et protein som er viktig for tyreoideahormonregulering av hjernen. Proteinet transporterer skjoldbruskkjertelhormon over blod-hjerne-barrieren; det vil si fra blodet utenfor hjernen til blodet inne i hjernen. Transthyretin som transporterer skjoldbruskkjertelhormonet i blodet produseres i leveren, men transtyretin som transporterer skjoldbruskkjertelhormonet gjennom blod-hjernebarrieren produseres i en struktur som kalles "choroid plexus" ved bunnen av hjernen. Når jeg sier at proteinet transporterer skjoldbruskkjertelhormonet over blod-hjerne-barrieren, mener jeg at det transporterer både T4 og T3. Dette er viktig å forstå. Årsaken er at mange klinikere feilaktig tror at transtyretin bare transporterer T4 inn i hjernen. Basert på denne feilaktige troen, tror disse klinikerne også feilaktig at normal hjernefunksjon avhenger av pasienter som inkluderer T4 i skjoldbruskkjertelhormonbehandlingen. Dette er imidlertid åpenbart usant. (Andre steder dokumenterte jeg omfattende at transtyretin transporterer både T4 og T3 inn i hjernen. Jeg publiserte en artikkel i 2005 og den andre i 2006.) Du skrev at transthyretinnivået ditt var 0,20 g/l (20 mg/dL). Med et referanseområde på 0,18 til 0,39 g/l (18 til 39 mg/dL), er nivået ditt svært lavt; den er i den nedre fjerdedelen av området. Noen diagnostikere vil si at dette nivået betyr at du ikke produserer en optimal mengde transtyretin; andre vil si at du produserer mye. Jeg tror ikke vi har nok studier til å fortelle oss hvilke av disse diagnostikerne som har rett og galt. Det vi kan se fra nivået ditt er at du produserer proteinet og at du mest sannsynlig får skjoldbruskkjertelhormon inn i hjernen din. Vi har ikke kommersielt tilgjengelige tester som måler mengden skjoldbruskkjertelhormon som er bundet til ens transthyretin. Den informasjonen vil være verdifull. Årsaken er at dioksiner og PCB kan fortrenge skjoldbruskkjertelhormonet fra proteinet. Som et resultat kan disse kjemiske forurensningene ri inn i hjernen på proteinet. Jo flere av forurensningene som tar proteinet inn i hjernen, jo mindre er det sannsynlig at T4 og T3 når hjerneceller. Når de først er inne i hjernen binder dioksiner og PCB seg til T3-reseptorer på gener. Bindingen endrer mønsteret av koder som genene sender ut til arbeidsdelen av cellen for produksjon av proteiner. Jeg tror dette fenomenet er ansvarlig for noen av de kognitive og humørproblemene til mennesker som er forurenset med dioksiner og PCB, som toksikologer har fortalt meg er induviduelt. (Jeg dokumenterte mye av de skjoldbruskkjertelforstyrrende effektene av disse forurensningene i avsnittet "Miljøforurensninger" i kapittel 2.4, "Styreoideahormonmangel," i The Metabolic Treatment of Fibromyalgia [tilgjengelig i utgiverens E-kapitteldel].) Jeg antar at du skrev til meg om transthyretinnivået ditt av bekymring for skjoldbruskhormonstatusen din. Noen klinikere bestiller imidlertid testen for å finne ut om en pasient får i seg nok protein. Transthyretin er et "glykoprotein", som betyr at det er et karbohydrat kombinert med et protein. Av alle proteinene i blodet er det transthyretin som er mest nyttig for å fortelle om en person har proteinmangel. Halveringstiden til proteinet er omtrent to dager, så nivået i blodet endres raskt når noen markant reduserer eller øker proteininntaket, fordøyelsen og/eller absorpsjonen. Du sa ikke om du spiste lite eller ingen proteiner i flere dager før blodet ble tappet for å måle transthyretinet ditt. Hvis du spiste lite eller ingenting, kan det forklare det lave nivået av transtyretin. Hvis det er tilfelle, bør du snakke med legen din om å måle transthyretinnivået ditt igjen etter at du har spist 50 til 75 gram protein hver dag i flere dager. Trantyretinnivået ditt kan da være høyere. Men husk at betennelse og infeksjon også kan senke transtyretinnivået, og alvorlig nyresykdom og bruk av glukokortikoid (som prednison eller prednisolon) kan øke nivået ditt. Jeg håper dette er nyttig for deg. 8. desember 2008 Spørsmål: Jeg er så takknemlig for at jeg ble fortalt om ThyroidScience.com. Jeg leste artikkelen om "Weight Gain and the TSH" og sendte den til mine tre søstre som også lider av hypotyreose. Jeg begynte med Armour Thyroid-medisiner for nesten to uker siden og føler meg så mye bedre enn de siste 7 årene med levotyroksin. Jeg vet at dette er en positiv start i riktig retning for meg personlig. Jeg har 30 kilo å kvitte meg med som jeg har gått opp i løpet av de siste 7 årene etter to påfølgende svangerskap i 2002 og 2003. Takk for at du gjorde denne informasjonen tilgjengelig for folk (ikke bare leger) som er proaktive rundt helsen deres. Dr Lowe: Tusen takk for at du skrev til oss om at du føler deg bedre på Armour Thyroid etter å ha gått opp tretti kilo i vekt mens du bruker levotyroksin. Hvis du bruker en høy nok dose av Armour, forventer jeg at du vil miste de 30 ekstra kiloene du fikk i løpet av de syv årene du brukte levotyroksin. Dette er spesielt sannsynlig hvis du har et sunt kosthold og trener regelmessig. Armour Thyroid, som Nature-Throid og Westhroid, er mer effektiv enn levotyroksin til å redusere kroppsfett. Årsaken er at disse produktene inneholder T3. Noen forskere sier at T3 har en "lipolytisk" - det vil si en fettnedbrytende - virkning i fettceller.[3] En måte T3 reduserer fett i cellene på er ved å hemme et enzym (syklisk-AMP fosfodiesterase) som bremser stoffskiftet kort tid etter adrenalin og noradrenalin øker hastigheten.[1][3][8] Ved å blokkere dette enzymet opprettholder T3 den fettnedbrytende effekten av adrenalin og noradrenalin i fettcellene.[1][2][8] En annen måte T3 reduserer fett på er ved å endre gentranskripsjon for flere forbindelser. Når T3, som virker gjennom de relevante genene, øker fettcellenes produksjon av disse forbindelsene, forsterker forbindelsene adrenalins og noradrenalins fettsenkende effekt i cellene. [10] I tillegg til vekttap, kan du få en annen fordel av T3 i Armour: det vil si en reduksjon av fett som sannsynligvis har samlet seg i arteriene dine[3] mens du brukte T4-erstatning.[11] Som Duntas bemerket i 2002, er sammensetningen og transporten av blodfett "alvorlig forstyrret i skjoldbruskkjertelsykdommer." Blant pasienter med høyt TSH og lavt nivå av skjoldbruskkjertelhormon, er kolesterol og LDL vanligvis høye. Selv når thyreoideahormonnivåene er innenfor referanseområdet, men TSH er høy, har pasienter i gjennomsnitt et litt høyt totalkolesterol, høyt LDL og lavt HDL. Disse pasientene har også abnormiteter i slimhinnene i arteriene, betennelse og fettansamling i aorta, og de er utsatt for hjerteinfarkt. De har også økt motstand mot blodstrøm, svakere sammentrekninger av hjertemuskelen og øker det diastoliske blodtrykket. Som Duntas påpekte, fører skjoldbruskhormonbehandling - spesielt med TSH-undertrykkende doser - "vanligvis til en betydelig forbedring i lipidprofilen." T3 reduserer fett i arteriene delvis ved å øke aktiviteten til et enzym kalt "lipoproteinlipase."[4] Lav aktivitet av dette enzymet fører til høyt blodfett, som er en risikofaktor for koronar hjertesykdom.[7] Skjoldbruskhormon øker aktiviteten til enzymet, og ved å gjøre det reduserer det blodfettet.[4] Skjoldbruskhormon senker også LDL-kolesterol ved å øke antall LDL-reseptorer på leverceller.[11] I min kliniske erfaring er skjoldbruskkjertelhormonbehandling (med produkter som inneholder T3) langt mer effektiv enn statiner for å normalisere blodfett. Jeg tror at hvis pasienter generelt fikk lov til å bruke effektiv thyreoideahormonbehandling fremfor T4-erstatning, kunne vi praktisk talt eliminert markedet for statiner. Da ville pasienter være fri for potensielle bivirkninger av statinmedisiner, som kroniske muskelsmerter og andre smertesyndromer, forhøyede leverenzymer, perifer nevropati og muskelskade.[9] Fortell oss hvordan det går. Jeg ønsker deg lykke til. Referanser 1. Bégin-Heick, N. and Heick, H.M.: Increased response of adipose tissue of the ob/ob mouse to the action of adrenaline after treatment with thyroxin. Can. J. Physiol. Pharmacol ., 55(6):1320-1329, 1977. 2. Elks, M.L. and Manganiello, V.C.: Effects of thyroid hormone on regulation of lipolysis and adenosine 3',5'-monophosphate metabolism in 3T3-L1 adipocytes. Endocrinology, 117(3):947-953, 1985. 3. Mandel, L.R. and Kuehl, F.A., Jr.: Lipolytic action of 3,3'5-triiodo-L-thyronine, a cyclic AMP phosphodiesterase inhibitor. Biochem. Biophys. Res. Commun. , 28(1):13-18, 1967. 4. Pykälistö, O., Goldberg, A.P., and Brunzell, J.D.: Reversal of decreased human adipose tissue lipoprotein lipase and hypertriglyceridemia after treatment of hypothyroidism. J. Clin. Endocrinol. Metab ., 43(3):591-600, 1976. 5. Beisiegel, U.: Lipoprotein metabolism. Eur. Heart J. , 19 Suppl A:A20-A23, 1998. 6. Otto, W., Taylor, T.G., and York, D.A.: Glycerol release in vitro from adipose tissue of obese (ob/ob) mice treated with thyroid hormones. J. Endocrinol. , 71(1):143-155, 1976. 7. Salter, A.M. and Brindley, D.N.: The biochemistry of lipoproteins. J. Inherit. Metab. Dis ., 11 Suppl 1:4-17, 1988. 8. Wahrenberg, H., Wennlund, A., and Arner P.: Adrenergic regulation of lipolysis in fat cells from hyperthyroid and hypothyroid patients. J. Clin. Endocrinol. Metab ., 78(4):898-903, 1994. 9. Brown, W.V.: Safety of statins. Curr. Opin. Lipidol ., 19(6):558-562. 2008. 10. Viguerie, N., Millet, L., Avizou, S., et al.: Regulation of human adipocyte gene expression by thyroid hormone. J. Clin. Endocrinol. Metab. , 2002 Feb;87(2):630-634, 2002. 11. Duntas, L.H.: Thyroid disease and lipids. Thyroid , 12(4):287-293, 2002. 16. november 2008 Spørsmål: Har rapporten nedenfor virkelig blitt gjennomgått???? http://www.thyroidscience.com/studies/overbye.2007/overbye.metabolicfailure.fms.lowethesis.pdf Jeg stiller ikke spørsmål ved Lowe-hypotesen, men jeg mener at en så dårlig rapport som denne faktisk skader saken – spesielt om metodene som brukes ikke er støttet opp med kjente eller aksepterte metoder. Dr Lowe: Takk for e-posten og omtanken din. Ja, faktisk: Dr. Øverbyes rapport ble gjennomgått. Flere av fagfellene våre leste artikkelen, og hver av dem anbefalte på det sterkeste at vi publiserer den. Som en av anmelderne kommenterte etter å ha sett gjennom Dr. Øverbyes manuskript, "Denne artikkelen rapporterer om den typen banebrytende, kreativ pilotforskning som vi ønsker å oppmuntre." Du antyder at Dr. Øverbyes rapport er "dårlig" fordi metodene hans "ikke ble støttet opp med kjente eller aksepterte metoder." I konvensjonell medisin har selvfølgelig kreativ forskning ved bruk av innovative metoder tradisjonelt blitt frarådet. Husk påstanden: "Vær ikke den første som prøver noe nytt, og heller ikke den siste som legger det gamle til side." Vi i Thyroid Science avviser denne fremgangskvelende, flokkmentalitetsorienteringen. I stedet oppmuntrer vi originale og progressive kliniske metoder og forskning. Den orienteringen er eksemplifisert ved at Thyroid Science publiserte Dr. Øverbyes artikkel. Selv om denne orienteringen for noen mennesker kan fremstå som ukonvensjonell, står vi fast ved den siden vi tror at denne orienteringen sannsynligvis vil gi hjelp til millioner av skjoldbruskkjertelpasienter som konvensjonell medisin fortsatt ikke hjelper. Din vurdering av Dr. Øverbyes studie og hans rapport bringer tankene til lignende bemerkelsesverdige hendelser. For eksempel professor Linus Pauling, en to ganger nobelprisvinner rangert blant de ti mest premierte forskerne i historien. Pauling var også dyktig i sine vitenskapelige undersøkelser innen ernæring. Men redaktører av medisinske tidsskrifter sensurerte ham ofte ved å avvise eller utsette publisering av manuskriptene hans fordi innholdet utfordret konvensjonelle medisinske fordommer. (For å lese beskrivelsen hans av sensur fra redaktører – inkludert redaktøren av Journal of the American Medical Association – les kapittelet hans med tittelen "Organized Medicine and the Vitamins" i boken hans med tittelen How to Live Longer And Feel Better.) Derimot, etter en viss motstand tidlig i karrieren, aksepterte kjemitidsskrifter Paulings tenkning og metoder som klart var utenfor grensene til «boksen». Noen redaktører godtok manuskriptene hans som inneholdt ekstremt nyskapende materiale uten å sende dem til fagfellebedømmere. Som en redaktør bemerket, var fagfellevurdering umulig ved at Pauling ikke hadde noen jevnaldrende. Kjemifaget fikk fordelen av Paulings fantasifulle og innovative sinn. Jeg sier ikke at Dr. Øverbyes artikkel er garantert å ha den enorme vitenskapelige betydningen som mange av Paulings artikler (selv om jeg heller ikke sier at det motsatte). Det jeg sier er at Thyroid Science ikke vil sensurere forskning bare fordi den involverer gjennomtenkte, friske ideer og innovative metoder. Som i Dr. Øverbyes tilfelle, oppfordrer vi forskere til å bruke veletablerte teknologier fra andre felt for å gjøre vitenskapelige fremskritt innen medisin. Han har gjort det, og på en beundringsverdig måte. Vi setter pris på at du uttrykker din mening og tillater oss å forklare hvorfor våre anmeldere og redaktører entusiastisk godkjente Dr. Øverbyes artikkel for publisering. 23. februar 2008 Spørsmål: Er du klar over papiret av E Tjørve, KMC Tjørve, JO Olsen, R Senum, H Oftebro med tittelen "On commmonness and rarity of thyroid hormon resistance: A discussion based on mechanisms of redusert sensitivity in periferal tissues" (Medical Hypotheses, (2007) 69, 913-921)? I den etterlyser forfatterne en test for perifer motstand. Siden standardblodprøver ikke tjener dette formålet. Kanskje finnålsaspirasjonsteknikken (FNA) som ble brukt av Dr. Bo Wikland og hans kolleger ville passe her? Dr Lowe: Jeg har lest E Tjørves rapport. Jeg er glad for at Dr. Tjørve og hans medforfattere nevnte måling av basalstoffskiftet som en metode for å teste for resistens. Jeg har brukt testen i min kliniske praksis i flere år og publisert to studier så langt med metoden: Rapport hos Medical Science Monitor: http://www.medscimonit.com/abstracted.php?level=4&id_issue=40182 (Når du kommer til siden på Medical Science Monitor, bla ned til den andre artikkelen under "Klinisk forskning".) Rapport hos Thyroid Science : http://www.thyroidscience.com/studies/lowe.2006/lowe.2nd.rmr.fms.htm Så som Tjorve et al, tror jeg at basal- eller hvilemetabolsk ratemåling er mest nyttig klinisk for å identifisere resistenspasienter, i hvert fall de med perifer resistens. (Å ha perifer motstand betyr selvfølgelig at en pasients hypofyse normalt eller nesten normalt reagerer på thyroidhormon, men de fleste vev perifert til hypofysen er delvis resistente.) Dr. Wiklands FNA identifiserer pasienter som har autoimmun tyreoiditt til tross for referanseområdet antithyroide antistoffnivåer. De fleste av pasientene er hypothyroide, som er grunnen til at han og hans kolleger kaller lidelsen "subklinisk hypotyreose." Noen av disse pasientene kan også ha perifer resistens. Men hvis de forbedrer seg eller blir friske med doser av skjoldbruskhormon som er lavere enn suprafysiologiske mengder, vil det tyde på at de bare er hypothyroide og ikke resistente. De fleste pasienter med skjoldbruskhormonresistens må bruke suprafysiologiske doser av T3 for å bli friske. Selv T4/T3-produkter som Armour fungerer vanligvis ikke for dem, ikke med mindre de bruker store doser, for eksempel 12 grains eller mer. Jeg har en bok utgitt i 1962 skrevet av en endokrinolog – en endokrinolog fra tiden da mange av dem praktiserte klinisk medisin i stedet for den ekstremistiske teknokratiske medisinen til de fleste endokrinologer i dag. I boken skrev endokrinologen at noen av hans "hypotyreosepasienter" ikke ble friske før de tok så mye som 60 grain "tørket skjoldbruskkjertel" per dag. Jeg antar at disse pasientene virkelig hadde perifer resistens, siden den mengden ville inneholde omtrent 540 mcg T3. Det er virkelig en suprafysiologisk daglig dose! Som meg, har Dr. Wikland funnet ut at de fleste hypothyroidpasienter må ha supprimert TSH-nivå før de blir friske. Jeg vet ikke hvilke doser pasientene hans vanligvis bruker, men hvis noen av dem bruker doser som ligger godt innenfor det suprafysiologiske området, er pasientene sannsynligvis delvis resistente mot skjoldbruskhormon. Jeg bruker følgende kriterier for å diagnostisere perifer resistens: pasienten har før behandling (1) hypothyreoidea-lignende symptomer før behandling, (2) referanseområde TSH og skjoldbruskhormonnivåer, og (3) en unormalt lav hvilemetabolsk hastighet; og etter behandling, han eller hun (4) kommer seg etter symptomene sine med en suprafysiologisk dosering av vanlig T3 (5) uten tegn på tyreotoksikose. Det finnes laboratoriemetoder for å teste for resistens. For eksempel kan vi bruke fibroblaster fra en pasients hud. Hvis en suprafysiologisk mengde T3 er nødvendig for å hemme fibroblastenes syntese og sekresjon av bindevevsbestanddeler som fibronektin, er pasientens celler (i det minste hans eller hennes fibroblaster) resistente mot skjoldbruskkjertelhormon. Jeg bruker ikke denne testen av to grunner: For det første er den ikke kommersielt tilgjengelig; og for det andre, selv om det var det, krever det en smertefull punch-biopsi av huden som jeg foretrekker å ikke utsette pasienter for. For å oppsummere kan Dr. Wiklands FNA sikkert identifisere pasienter som er hypothyroide på grunn av autoimmun tyreoiditt. Imidlertid vil prosedyren ikke identifisere eller utelukke perifer motstand mot skjoldbruskkjertelhormon.

Skrevet av Dr. John Lowe, MA, DC og The Thyroid Patient Advocacy UK Originalspråk: Engelsk http://thyroidscience.com/Criticism/lowe.dec.2006/lowe.critique.T4.T4.T3.studies.pdf Dr. John C. Lowe, en mangeårig forsker innen hypotyreose, hypometabolisme, fibromyalgi og bruk av T3-medisiner for skjoldbruskkjertelen og metabolske tilstander, har publisert en banebrytende analyse som bør leses. Han har sett på de fire studiene som nylig ble publisert i store medisinske tidsskrifter, som alle var fullstendig kritiske til bruken av T3. Dr. Lowe har dekonstruert forskningen og påpekt de mange store feilene - feil som vil tvinge legen din til å revurdere gyldigheten av de tidligere funnene. For enhver skjoldbruskkjertelpasient som ikke føler seg bra på T4 (levotyroksin, dvs. Synthroid) alene, oppfordrer jeg deg til å skrive ut PDF-versjonen av analyserapporten og ta den med til legen din. Og hvis du har en lege eller endokrinolog som har avvist T3 på grunn av den nyere forskningen, så enda mer grunn til å sørge for at du deler en kopi av Dr. Lowes artikkel, Thyroid Hormone Replacement Therapies: Ineffective and Harmful for Many Hypothyroid Patients. Du kan også lese en versjon på nettet. Så, en spesiell melding fra Dr. Lowe: For et halvt år siden publiserte medisinske tidsskrifter fire studier av endokrinologer som vekket oppmerksomhet i det alternative medisinmiljøet. I studiene sammenlignet endokrinologene effektiviteten av T4-erstatning med kombinert T4/T3-erstatning. "Erstatning" refererer selvfølgelig til doser av skjoldbruskkjertelhormon som holder TSH-nivået innenfor det nåværende laboratoriereferanseområdet. Å ha denne definisjonen i bakhodet er avgjørende for å forstå hva de fire studiene faktisk viste, og hva de ikke viste. Hva studiene viste er dette: Ingen av formene for erstatningsterapi lindret hypothyreoideapasienters symptomer eller unormale testresultater. Faktisk er de fire studiene bevis positive til at erstatningsterapi etterlater mange hypothyroidpasienter i lidelse. De fleste av forskerne rapporterte nøyaktig dette negative behandlingsfunnet. Funnet er imidlertid dypt begravet i deres publiserte fulltekstrapporter; for å se at den er der, må man først få en kopi av tidsskriftsartiklene - noe de fleste leger og pasienter ikke vil gjøre - og deretter lese nøye. I motsetning til hva de fant, sendte endokrinologene tydeligvis noe de ikke fant: at ingen tilnærming til T4/T3-terapi er mer effektiv enn T4 alene. Som jeg forklarer i detalj i min kritikk, er forskjellen mellom hva de fant og hva de ikke fant ingen liten forskjell; det kan alvorlig påvirke den kliniske behandlingen av hypothyroidpasienter. De falske rapportene fra endokrinologene er nesten sikre på å implantere en falsk tro i hodet til leger. Som et resultat vil legene sannsynligvis begrense millioner av hypothyroidpasienter til T4-erstatning til tross for studiene som viser at det er ineffektivt for mange pasienter. De fire studiene så ut til å være et svar fra endokrinologisk spesialitet og dets bedriftssponsorer på en studie publisert i 1999 i New England Journal of Medicine.[1] I den studien rapporterte forskere et funn som truet markedet for T4-erstatningsterapi. Funnet var at tilsetning av T3 til hypothyroidpasienters daglige T4-dose forbedret deres kognitive funksjon. Som et resultat av den studien begynte mange hypothyroidpasienter å spørre legene sine om å legge til T3 til T4 de allerede tok. Resultatet av de fire 2003-studiene – som kombinert T4/T3-erstatning ikke var mer effektivt enn T4-erstatning – motsier resultatet fra 1999-studien. Noen få alternative skjoldbruskkjertelleger kritiserte noen av studiene fra 2003. Hovedstedet deres kritikk ble publisert var thyroid.about.com - nettstedet til skjoldbruskkjertelpasientens talsmann Mary Shomon, der den demokratiske ånden utøves ved publisering av avvikende synspunkter. Imidlertid ble ingen kritikk av studiene publisert i noe større medisinsk tidsskrift. Dette var absolutt ingen overraskelse for oss ved Fibromyalgiforskningsstiftelsen. Forskerteamet vårt lærte for lenge siden at sidene til store medisinske tidsskrifter nesten alltid er stengt for skjoldbruskkjertelforskere bortsett fra under én betingelse: når de rapporterer studieresultater som støtter fordommene til endokrinologisk spesialitet til fordel for T4-erstatning. Hvis et forskningsteams studiefunn ikke er gunstig for T4-erstatning, kan teamet like gjerne glemme å sende inn rapporten til et større medisinsk tidsskrift - det er ekstremt usannsynlig at den vil bli akseptert for publisering. Et virkelig sjeldent unntak var studien fra 1999 som rapporterte at T4/T3-erstatning var mer effektiv enn T4-erstatning. Jeg lurer fortsatt på hvordan den rapporten gled forbi endokrinologisk spesialitets sensorer. Hovedredaksjonene om de fire 2003-studiene i store medisinske tidsskrifter ble skrevet av endokrinologer. I hver av lederne gjentok endokrinologene de falske rapportene fra endokrinologene som utførte studiene. Vi har publisert min kritikk av de fire studiene på drlowe.com. Kritikken er en formell logisk analyse med etiske implikasjoner. Hensikten med kritikken er tredelt: (1) å forklare feilslutningen i endokrinologiforskernes rapporter; (2) å bevise at for mange pasienter er T4-erstatning både ineffektiv og skadelig; og (3) å stille spørsmål ved endokrinologens motiv for å gi råd om at T4-erstatning forblir den foretrukne behandlingen, til tross for studiene som viser at den er ineffektiv for å lindre mange pasienters symptomer. Jeg sender varsel om kritikken til disse endokrinologiforskerne og endokrinologene som skrev lederartikler som gjentok den falske konklusjonen. Vi vil informere leserne våre om innholdet i alle svar jeg mottar fra dem. Jeg vil takke redaktøren min, Jackie Yellin, for å ha jobbet lenge og hardt med meg for å gjøre kritikken klar og logisk presis. Jeg vil også takke Michael Yellin for hans kresne korrekturlesing. Jeg takker også Mary Shomon for å varsle leserne om kritikken. Hun forteller meg at hun vil råde pasienter som er begrenset til T4-erstatning og fortsatt lider av hypothyreoideasymptomer om å skrive ut kritikken som en pdf-fil og ta den med til sine forskrivende lege. Leger som leser det vil vite hvorfor pasientene deres fortsetter å lide av hypothyroidsymptomer til tross for at de bruker T4-erstatning. Legene vil også være klar over at det å begrense pasientene til T4-erstatning kan øke stoffbruken deres og sette dem i fare for flere sykdommer som kan føre til for tidlig død. Referanse: [1] Bunevicius, R., Kazanavicius, G., Zalinkevicius, R., and Prange, A.J. Jr.: Effects of thyroxine as compared with thyroxine plus triiodothyronine in patients with hypothyroidism. N. Engl. J. Med., 11;340(6):424-429, 1999.

Skrevet av Dr. Bjørn Øverbye, 2007 Originalspråk: Norsk I perioden 1892-1958 fantes kun ett legemiddel mot stoffskiftesvikt: Natural Desiccated Thyroid (NDT). Legene definerte i denne perioden "lavt stoffskifte" som en gruppe lidelser man kunne identifisere via pasientens symptomer og grundig legearbeid, og som ble bra eller bedre med NDT. Her er hvordan man tenkte den gangen: Kjærlighet til kunnskap La det være klart fra starten av: Dette er ikke et nettsted med reklame for bruk av Natur Thyroid (NDT) til fordel for syntetiske hormoner. Når vi tar opp temaet NDT er det ene og alene fordi vi søker etter kunnskaper om hvorfor fortidens leger kunne rapportere så mange positive resultater med NDT før man i det hele tatt fikk kommersielt tilgjengelige syntetiske hormoner. Når bruken av syntetisk hormoner kom i allment bruk er uklart. Men det er kjent at Thyroxin Natrium ble registrert i Norge i 1950 og Synthyroid i USA 1958 . Tillot norske myndigheter dårlig legemiddel i 8 år? Så i Norge regnes 1950 som året da «den nye tiden startet». Dette årstallet er beheftet med en noe besynderlig opplysning. Ifølge Amerikansk Legemiddelkontroll (FDA) var Thyroxin-Natrium et ikke FDA-godkjent legemiddel før år 2000 fordi dets virkemåte var dårlig. Dette kan bety at Norsk Legemiddelkontroll i 8 år tillot benyttet et ikke FDA-godkjent legemiddel av dårlig kvalitet for hypothyreose. Enda mer underlig: Det ser ut til at myndighetene i mange delstater tross dette tillot salg av Thyroxin-Natrium. I dag, 50 år senere anser man i USA at det først i 1958 kom syntetisk thyroxin av god kvalitet på markedet som kunne konkurrere med NDT. Det gode produktet ble kalt Synthyroid. (Steven B Johnson, Division of Pharmaceutical Evaluation Phase II-FDA, 13 March 2003) Vi har derfor i dette nettstedet valgt å bruke 1958 som året da pålitelig syntetisk thyroxin (T4) ble kommersielt tilgjengelig, som det året da NDT fikk en troverdig konkurrent. Et problem som bygger på en misforståelse Utgangspunktet for vår søken er å forstå hvilken type legearbeid man bedrev i perioden 1892-1958 da NDT var det eneste terapitilbudet og som ledet legene til å si at de observerte bedringer hos stoffskiftesyke. Hva var det de gjorde som ledet til helt andre konklusjoner enn det motstandere av NDT kommer med nå i nyere tider? I denne sammenheng gjør vi en klar reservasjon: Vi tror ikke på enhver lovprisning fra fortiden. Vi tar takhøyde for datidens begrensede laboratorietjenester. Vi innser at dagens «gullstandard» dobbeltblindede placebo-kontrollerte forsøk ikke var mulig å gjennomføre fordi: Man hadde bare ett preparat av god kvalitet mot stoffskiftesvikt, nemlig NDT, frem til 1958. (Thyroxin-Natrium kom på markedet i Norge i 1950, men i USA angis "på 50 tallet") Placebo-testing ble ikke brukt, da det ville bli avslørt med en gang. Det er fordi om man har hormonsvikt, merker man at det dreier seg om narrepiller på grunn av at de ikke kan fremkalle en hormoneffekt. Vi kan derfor ikke som mange gjør, klandre fortidens leger for ikke å gjøre som i dag. Situasjonen var rent ut sagt usammenlignbar. Det som fantes av forskning må kun vurderes hvorvidt det var godt eller dårlig legearbeid. Det er resultatene fra de legene som drev med godt legearbeid vi vil undersøke, for å se om de kan gi oss svar på hvor bra NDT var. Hengivenhet mot bevisbare fakta Det er noe som slår en når man leser de positive uttalelsene til fordel for NDT fra 1920 og utover, da leger som O. P. Kimball (1933), G. K. Wharton (1939), og siden B. Barnes (1976) og en rekke andre fremragende leger gjorde sine observasjoner, nemlig dette ene faktum: De gode legene var trofaste mot en yrkesetikk som gikk på hengivenhet mot virkeligheten. De flinke legene var tro mot virkeligheten ved at de hadde tiltro til de sykes fortellinger og endringene de så i pasientens kropp, som de betegnet som myxedema i en eller annen utgave/grad. Dernest anså de det som deres moralske forpliktelser å bruke det legemiddel de hadde tilgjengelig, NDT, i slike doser at de observerte gradvis forbedring hos de syke (Barnes 1976). For det tredje: Legene arbeidet forsatt i en tidsalder da legevitenskap ikke ble betalt av legemiddelindustrien for å bevise at bestemte kjemiske industriprodukter skulle ha et fortrinn overfor andre produkter. Det fantes kun NDT. Først observere, så konkludere Legene som drev forskning og noterte erfaringer med NDT beskriver hvordan de vurderte effekten ved å lytte til hva pasientene fortalte om subjektive bedringer (symptomene) (Barnes side 24) Videre, ved å iakkta og berøre pasientene beskriver de hvordan observere endringer i pasientens kroppsform og kroppens konsistens (tegn). I tillegg, å måle muskelstyrke. De beskriver hvilke målinger de gjorde for å søke målbare effekter av terapi slik som: Vekt Måle blodtrykk. Lytte på hjertet Ta EKG (tilgjengelig allerede for 120 år siden) Woltman's tegn: Forsinket hel-sene-refleks (oppdaget i 1870) Måle temperaturen (siden 1920-tallet) Gjøre målinger av visse blodverdier som endrer seg med stoffskiftet slik som kolesterol, kalk-indeksen, blodsukker-belastningskurven mm. Legene hadde således gode metoder for å observere endringer som følge av inntak av NDT og de doserte tablettene slik at endringene ble stadig mer lik det vi ser hos friske. Hormontester i blodet kom først mye senere Kommersielle målinger av tyroksin i blodet kom først på 1960 tallet. Testen for fritt tyroksin kom i 1965. I 1975 kom kommersielle tester for TSH, men først i 1985 ble TSH-testene brukbare. Men så sent som 1992 var det stor uenighet blant kjemikere og leger om de mest brukte Fritt T4-testene, om de i det hele tatt var brukbare i klinisk arbeid. Diskusjonen angående om Fritt T4 og TSH var i samsvar med fakta, fortsatte helt frem til 2009 (John Midgely 2014). Dette betyr at helt inn i vårt århundre var mye av såkalt «moderne thyroidforskning» beheftet med store problemer og at det å feste all tillit til laboratorieverdier ikke var så bra som mange idag tror. Leger må lære av atomfysikken De første generasjoner thyroidealeger var derfor avhengige av å observere resultater av handlinger. Dette er også i samsvar med en annen oppdagelse som ble gjort i slutten av det nittende århundre innen atomfysikken og som gjorde fysikken til en strålende suksess: Fysikeren innså at man ikke kunne uttale seg om noe før det har skjedd. (Feynmann 1963) I fysikken ble man klar over at ingen kan forutsi hva som skal skje på atomnivå uten målinger. Dette var grunnen til mange oppfinnsomme atomteorier som ble laget før man hadde gode målinger ble forkastet, fordi de oppfinnsomme teoretikerne ikke kunne fremlegge målinger som støttet deres antagelser. (Feynmann 1963) Fysikerne forstod at man må måle det man skal uttale seg om, hva enn det måtte være. Dette ble grunnpillaren i fysikken. Man kan ikke lage en teori/tankebilder ledsaget av matematiske modeller, før man har måledata. Derfor var samtidens fysikere forferdet da Einstein uttalte at mystiske opplevelser var en vei til erkjennelse. Dette gjorde at Einstein ikke fikk Nobelprisen for sin relativitetsteori, fordi han hevdet å ha konstruert den på prinsipper som enda ikke var forklart ved måling. Han fikk det derimot for forklaringen på Planck's foto-elektriske forsøk. Medisin er ikke vitenskap før man har observert Dette vil nødvendigvis også gjelde medisinen, man kan ikke uttale seg om et legemiddel før man har målt dets effekt på den enkelte pasient. Deretter må observasjonene kunne beskrives i et forståelig språk som peker på en erkjennbar virkelighet. (Korzybski 1994) Siden menneskers evne til å reagere på et legemiddel avhenger av en rekke faktorer, vil den målte og observerte effekt avhenge helt og holdent av hva pasienten opplever og legen registrerer. Det er derfor bortimot umulig å bedrive medisinsk virksomhet, dosere syke med standarddoser, og glemme basen for objektiv materialistisk vitenskap, nemlig iakttagelsesevne. Legen må lære opp syke til å forstå hva som skjer i egen kropp slik at pasienten kan meddele til legen hva som skjer. Deretter må legen iakkta det som skjer. (Skrabanek og McCormick). Man kan ikke føre noen meningsfylt samtale om NDT kontra Thyroxin og hvorvidt det ene er bedre enn det andre. Man kan kun fastslå de observasjoner som er gjort av den syke selv og av legen med legeverktøy. Derfor, i følge professor Broda Barnes og flere med ham; uten nøyaktig observasjon gjort av syke og av lege med sine verktøy, ingen grunnlag for troverdig meningsytring i en debatt eller i argumentasjon ovenfor pasienter og kollegaer. Viderefører vi denne logiske betraktning, så spør vi deg som leser dette; Blir en person bedre med syntetisk hormon enn med NDT? Hva skal denne personen da bruke? Blir en annen kun bedre med NDT og ikke med syntetisk hormon, hva skal denne personen bruke? Vi overlater konklusjonene til leseren, fordi dette var ment som en oppsummering av historiske fakta og ikke en diskusjon om det ene kontra det andre.