2 GENERAL CONSIDERATIONS MUST WORK FOR HUMANS TO FUNCTIONABSORPTION AND ASSIMILATIONDETOXIFICATION AND ELIMINATIONREGULATIONSTRESS IMPACTS ALL OF THESE BUT THE MOST PROFOUND AND IMMEDIATE EFFECT IS ON REGULATIONADRENAL AND THYROID GLANDS ARE THE MOST STRESS LABILEADRENAL AND THYROID INTERACT IN REGULATINGWEIGHTENERGYBLOOD SUGARBLOOD FATSNEUROTRANSMITTERSSEX HORMONESINFLAMMATIONIMMUNE FUNCTION
3 ORGAN RESERVESUPPORTORGANRESERVEDegenerationSTRESSORS
4 Thyroid Feedback Regulation The production of thyroid hormone is controlled by a feedback loop. When there is not enough receptor site activity in the hypothalamus, TRH is elaborated which stimulates the anterior pituitary to make TSH, which then stimulates the thyroid to make more T3 and T4.The thyroid gland usesL-Tyrosine and Iodine to make T4, the storage form of thyroid hormone and T3 the active form
5 SUBCLINICAL HYPOTHYROID SYMPTOMS COMPATIBLE WITH HYPOTHYROID (> 12 on Symptom Survey)LOW BBT (< 97.5o F axillary)SLOW REFLEXES (> 137 msecs)LOWER RMRNORMAL TO SLIGHTLY HIGH TSHNORMAL FREE T3, FREE T4NORMAL T3U, T4, T7PREVALENCE UNKNOWN (8-30%)
7 DIABETES RISK DISRUPTION OF GLP-1 SIGNALLING DECREASED THYROID FUNCTION UP TO 18 HOURS AFTER HYPOGLYCEMIC EPISODESASSOCIATED WITH INSULIN RESISTANCEINCREASEDHOMA AND TRIG/HDLDYSGLYCEMIAOBESITY
8 ARTHRITIS & INFLAMMATION INCREASED RATES OF HASHIMOTO’SINCREASED EUTHYROID SICK RISKRA PATIENTS WITH SUBCLINICAL HYPOTHYROID HAD DYSFUNCTIONS OF GLUCOSE METABOLISM AND INSULIN RESISTANCEDessein showed that in rheumatoid arthritis patients, subclinical hypothyroid patients had dysfunctions of glucose metabolism and insulin resistance. Innocencio showed that 52% of systemic sclerosis and 32% of rheumatoid arthritis patients also had anti-thyroglobulin and/or anti-thyroperoxidase antibodies. This finding of silent autoimmune thyroiditis may contribute to the euthyroid sick syndrome seen in people with autoimmune diseases.20, 23
9 NEURO-PSYCHOLOGICAL RISK INCREASEDHOFFMAN’S SYNDROMEWEAKNESS AND STIFFNESSDUPUYTREN’S CONTRACTURECARPAL TUNNEL SYNDROMEPOLYMYOSITIS-LIKE SYNDROMEPARKINSONSHEARING LOSSANXIETY AND DEPRESSION1.97 RELATIVE RISK OF COGNITIVE DECLINE (ALZHEIMER’S)
10 (TAKE THYROID AT LEAST 45 MINS AWAY FROM CALCIUM) BONE RISKINCREASEDBONE RESORPTION IN HYPERTHYROIDURINARY PYRIDINOLINEURINARY DEOXYPYRIDINOLINEURINARY CALCIUMSERUM TELOPEPTIDESNO CALCIUM METABOLISM PROBLEMS IN HYPOTHYROIDCALCIUM BINDS THYROID(TAKE THYROID AT LEAST 45 MINS AWAY FROM CALCIUM)
11 PREGNANCY FERTILITY ISSUES 3 FOLD INCREASE IN PLACENTA PREVIA 2 FOLD INCREASE IN PREMATURE DELIVERYMAY AFFECT MENTATION IN OFFSPRINGNOT WELL STUDIEDCasey recently reported a three fold increase in placenta previa and a two fold increase in premature delivery in pregnant women with subclinical hypothyroidism.
12 FACTORS AFFECTING THYROID FUNCTION PERIPHERAL CONVERSION OF T4 TO T3HEPATIC, RENAL, MITOCHONDRIAL FUNCTIONDECREASED 5’D-1INHIBITED BY IL-1, IL-6TOXIC MATERIALSLEAD, MERCURYPCBFUNGICIDES, ORGANO-CHLORINE INSECTICIDESDRUGSAMIODORONE, ANTI-CONVULSANTS, SALSALATE, LITHIUMMITOCHONDRIAL PROTEIN LEAKAGEUNCOUPLING PROTEIN 3CYTOKINESNF-KAPPA-BTNF-ALPHAIL-1 ALPHA/BETAEUTHYROID SICK SYNDROME IMPAIRS FUNCTION UP TO 60 DAYS FOLLOWING ACUTE SEVERE ILLNESSPeripheral Conversion of T4 to T3Thyroid hormones are metabolized in peripheral tissues by deiodination, conjugation, deamination and decarboxylation enzyme reactions. Hepatic and renal pathology as well as stress states impact peripheral enzyme pathways. Toxic metals, chemical poisons, several drugs and nutrients may impact peripheral conversion. Vondra showed that there was a relationship between thyroid function and enzymes involved in glycolysis and cytoplasmic H2 transport from NADH2.Environmental ToxinsRat studies by several investigators showed that PCB exposure resulted in severely decreased serum T4 and moderate decreases in serum T3. Tomasi showed that in rats exposed to fungicides there was a decrease in thyroid hormone and that there was a corresponding increase in T3 turn-over. Pelletier proposed that organochlorine pesticide residues residing in adipose tissue would be released and cause a decrease in thyroid function in obese individuals during weight loss programs. Garry studied pesticide applicators and found subclinical hypothyroidism in 5/144. Guven found that 31.8% of patients who had been poisoned by organochlorines had Euthyroid Sick SyndromeMedicationsSeveral authors have shown that seizure medications and lithium reduce thyroid function. Amiodorone has been implicated in thyroid dysfunction. Wang showed that a single dose of salsalate caused a decrease of T3 and T4 as well as an increase in reverse T3 which lasted up to 96 hrs. It was concluded that there was an acute release of T4 and T3 from circulatory transport proteins induced by an inhibitor of binding. This resulted in a large and rapid redistribution of T4 and T3 into tissue compartments associated with transiently reduced peripheral tissue 5’monodeiodination and deranged TSH regulation.76Mitochondrial Proton LeakagePorter showed that mitochondrial proton leakage was related to uncoupling protein 3 (UCP3). de LP, et al showed that UCP3 is regulated by T3 and causes mitochondrial uncoupling affecting RMR. Reitman showed that free fatty acids appear to regulate UCP3 expression. Yu demonstrated that in euthyroid sick syndrome there is a decrease in activity of type 1 iodothyronine-5’-deiodinase (5’D-I) hepatic enzyme conversion of T4 to T3. This is believed to be a competitive inhibition by cytokines (IL-1 and IL-6). Hoch demonstrated that thyroid states regulate each cardiolipin property, and are permissive, via the proton antenna, for proton leaks. Slow leakage in liposomes may be due to insufficient cardiolipin proton antennas.38-42Stressed States and Euthyroid Sick SyndromeSchultes found that after a single episode of hypoglycemia, free T3 and free T4 were diminished and TSH increased up to 18 hours. Several investigators have found that in the Euthyroid Sick Syndrome and other stress states, that thyroid function is severely decreased. 22, 43-48CytokinesYu demonstrated that Interleukins 1 and 6 competitively inhibit the T3 induction of 5’deiodinase RNA and enzyme activity in rat hepatocytes. Nagaya, et al showed that activation of NF-kappa-B by TNF-alpha (which is elaborated in stress states) impairs T3 dependent induction of 5’deiodinase gene expression, which contributes to the Euthyroid Sick Syndrome. Rasmussen demonstrated that IL-1 alpha/beta in moderate and high concentrations reversibly inhibit thyroid cell function; while iL-1 beta in small doses stimulates thyroid cell function. This may contribute to the Euthyroid Sick Syndrome and/or autoimmune disease. The earliest stages involve antigen presenting cells interacting with the thyroid. In the later stages antigen specific and non-antigen specific immune cells are recruited to the thyroid and an inflammatory infiltrate is built. During this process cytokines, free nitric and oxygen radicals are released. Ren showed that Leukemia inhibitory factor (LIF), a neuroimmune pleiotropic cytokine is produced in the thyroid gland. TSH, IL-6, and glucocorticoid influence thyroid cell LIF expression. Kimur showed that IL-6 and IL-10 significantly correlated with TSH in acute MI patients that developed Euthyroid Sick Syndrome. Bagriacik demonstrated that serum T3 and T4 levels are sharply and transiently reduced during the first 24 hrs following systemic antigen exposure. These findings suggest that during the early phase of antigen exposure the immune system directly participates in the regulatory control of thyroid hormone activity.49-55
16 Vasoactive Intestinal Peptide and Thyroid Function VIP exerts action through 2 receptors VPAC1 and VPAC2VPAC1 receptors are in liver, breast, kidney, prostate, ureter, bladder, pancreatic ducts, GI mucosa, lung, thyroid, adipose tissue, lymphoid tissue, and adrenal medulla.VPAC2 receptors are in blood vessels, smooth muscles, the basal part of mucosal epithelium in colon, lung, and vasculature of kidney, adrenal medulla and retina. Also present in thyroid follicular cells and acinar cells of the pancreas.In hypothyroid, there was a 2-fold increase in all peptides derived from VIP, found in the gastric fundusIn hypothyroid significant increases of pituitary VIPVIP modulates T3 and T4 (decreases) in any inflammation
17 DE-IODINASES Tissues Site D1 rT3, T4, T3 D2 T4, rT3 D3 T3, T4 Type Bianco AC, Salvatore D, et al. Biochemistry, cellular and molecular biology,and physiological roles of the iodothyronine selenodeiodinases. Endocr Rev. 2002Feb;23(1):38-89.TypeTissuesSiteSubstratePreferenceInhibitorsD1Liver, Kidneys, ThyroidPlasma membrarT3, T4, T3PTU, T4+, IL1, IL6, TNFαD2Thyrotrophs, Hypothalamus, Skeletal Muscle, Heart, ThyroidEndo. ReticT4, rT3Iopanoate, T4+, T3+D3Brain, Placenta, Pregnant Uterus, SkinSubPlasmaMembT3, T4Iopanoate, DexamethasoneT4 to T3 CONVERSIONACTION ON METABOLISM
18 Thyroid Receptor Phenotypes Alkemade A, Vujist CL, et al. Thyroid hormone receptor expression in the humanhypothalamus and anterior pituitary. J Clin Endocrinol Metab Feb;90(2):TYPETISSUESTRβ2Pituitary ThyrotrophsTRβ1Liver, KidneyTRα1Skin, Muscle, HeartBrown FatTRα2BrainHypothalamus (inhibitory)T4 to T3 ConversionAction on Metabolism
19 TSH- REGULATION TRH TR-α2 D2, D3 TSH TR-β2 D2 T4, T3 TR-β2 ? D1, D2 T3 MAY NOT REPRESENT METABOLIC DEMANDTISSUEACTIONRECEPTORDE-IODINASEHYPOTHALAMUSBRAIN(action on metabolism)TRHTR-α2D2, D3THYROTROPHS(Pituitary)TSHTR-β2D2THYROID(T4, T3 production)T4, T3TR-β2 ?D1, D2LIVERKIDNEYS(T4 to T3 conversion)T3TR-β1D1SKELETAL MUSCLESHEARTTR-α1
20 NUTRIENTS AND THYROID SELENIUM IMPROVES FUNCTION DECREASES RECOVERY TIME IN EUTHYROID SICK SYNDROMEIRON AND ZINCINCREASE THYROID FUNCTION IN IRON/ZINC DEFICIENTNO EFFECT IN IRON/ZINC SUFFICIENTCALCIUMINHIBITS ABSORPTIONALPHA-TOCOPHEROLNO EFFECTKELP AND ALL IODINEHELPFUL IN IODINE DEFICIENTDOSE DEPENDENT DECREASE IN THYROID FUNCTION IF IODINE SUFFICIENTL-CARNITINE DECREASES THYROID FUNCTIONPREVENTS THYROID HORMONE ENTRY INTO NUCLEUS OF CELLSHigh Soy intake inhibits thyroid functionIpriflavone helps bone resorption but does not increase cancer risk
21 Lithium and Thyroid Function Enters thyrocyte via the Na+/I- SymporterConcentrated in thyroid gland to 3-4 times serum levelsIncreases intra-thyroidal iodine contentInhibits coupling of iodotyrosine residuesDecreases colloid droplet formationInhibits microtubule formationInhibits thyroid hormone secretionBlocks iodine release from thyroid glandTreats hyperthyroid in people allergic to iodine
23 STRESS ADAPTOGENS Hypercortisolemia Inhibits Thyroid Function HPT AXIS HPA AXISHPT AXISSTRESSHYPOTHALAMUSHYPOHYPERHYPOTHALAMUSTRHZINCCRHCRHADAPTOGENSINHIBITSSNSPITUITARYPITUITARYTSHACTHACTHINHIBITSADRENAL CORTEXTHYROIDSELENIUM, VIT DIODINE +/-MEDULLASELENIUM, ZINC, VIT E,ASWAGANDART3T4INHIBITSGLUCOCORTICOIDS(CORTISOL)GLUCOCORTICOIDS(CORTISOL)5’DEIODINASET3CATECHOLAMINES(EPINEPHRINE, NOREPINEPHRINE, ALDOSTERONE)Hypercortisolemia Inhibits Thyroid Function
24 Influence of Other Hormones on Thyroid Activity STRONGTHYROID STIMULATORSMILDTHYROIDSTIMULATORSINHIBITORSMILD THYROID INHIBITORSGrowth Hormone IGF-1 TestosteroneOther AndrogensDHEAAndrostenedioneMelatoninProgesteroneCortisol at physiologic dosesORAL ESTROGENS OF ANY TYPETransdermal or injectable Estradiol, Cortisol in small dosesInsulinIn patients with insulin deficiencyErythropoietin(hypothetical)Cortisol and otherGlucocorticoids at high doseIn patients with insulin resistanceHERTOGHE, T; The Hormone Handbook. International Medical BooksSurrey, UK, 2006, p88.
25 Hypothyroid Causes Adrenal Dysfunction Results in hypersecretion of CRH and AVP from hypothalamusSignificantly increased pituitary content of VIP↓ Adrenal weight, ↓ Corticosterone ACTH, CRH, AVPTohei A. Studies on the functional relationship between thyroid, adrenal and gonadal hormones. J Reprod Dev 2004 Feb;50(1):9-20.
26 MEASUREMENTS OF THYROID FUNCTION SERUM MEASUREMENTSWhat’s on the shelves at the pharmacyTSH INSENSITIVE WHEN APPROACHING NORMALPHYSIOLOGIC MEASUREMENTSWhat you took home from the pharmacyBODY MASS INDEXCORRELATION WITH RESTING METABOLIC RATEBASAL BODY TEMPERATURESIDENTIFY SUBCLINICAL HYPOTHYROIDTOO SLOW TO RESPOND TO TREATMENTRESTING METABOLIC RATESOME ARTIFACTSCONGESTIONREACTIVE AIRWAY DISEASEASTHMA OR OTHER COPDREFLEXESACHILLES, BRACHIORADIALIS, STAPEDIALNO ARTIFACTS UNLESS NERVE DAMAGEPhysiological Measurements Related to Thyroid FunctionMany investigators have used either estimations of resting energy expenditure such as the Harris-Benedict equations or direct measurements of resting metabolic rate to look at energy expenditure and energy requirements in a variety of populations. Many authors have demonstrated decrease in RMR with age and decreased thyroid function. Vondra showed the relationship between thyroid function and enzymes involved in glycolysis and hydrogen transport from NADH2, correlating achilles tendon reflexes and thyroid function. Khurana, Carel, Goodman and others have demonstrated statistically significant correlations between achilles tendon reflexes and thyroid function. Goulis demonstrated a similar effect using stapedial reflex. Findings have been consistent in a slowing of the firing interval of the reflex with decrease in thyroid function and a corresponding return to normal with treatment by thyroid medication. Body mass index, basal temps and other physical markers show some correlation. Being female and increasing age have shown correlations with thyroid dysfunction.40, 77-87Serum Thyroid TestsScobbo showed great variability in serum TSH depending on time of day samples were drawn and if the subject was fasted. Stockigt, et al showed that there was no current methodology that accurately reflects the free T4 in undiluted serum 88-90
27 METHODOLOGY ENTRY CRITERIA BBT<97.50 F AXILLARY AVERAGE (BRODA BARNES)BASELINE MEASUREMENT AND THIRTY DAY TREATMENT INTERVALSSYMPTOM SURVEYBODY MASS INDEXRESTING METABOLIC RATE (oxygen consumption)BRACHIORADIALIS REFLEXOMETRY (mean of 4)TSH,T3U, T4, T7ADDED FREE T3, FREE T4SOME HADMICROSOMAL (TPO) ABTHYROGLOBULIN ABREVERSE T3THYROTROPIN RELEASING HORMONELIPIDSCHOLESTEROLLDLHDLTRIGLYCERIDESRMR MEASUREMENTRMR was measured using the MedGem oxygen consumption device, which compared favorably to the Douglas Bag in clinical trials.[93-95]Risk of HyperthyroidismGussakoo found no correlation between plasma thyrotropin or free thyroxine in elderly patients with depression or cognitive dysfunction, but found that increased thyrotropin was correlated with increased longevity. Kisakol and others found that subclinical hyperthyroidism was associated with increased bone resorption, increased quality of life, increased lean body mass, increased functionality and increased longevity. 91, 92
28 RESTING METABOLIC RATE MEASUREMENT VIA OXYGENCONSUMPTION
42 WHY TSH DOES NOT IDENTIFY THOSE AT RISK !!! TSH gets too low before adequate effect (RMR)Patients that became normal by reflexes and symptoms had a mean RMR increase of about 400 kcalsN=100TSH <0.3FIRE-PREFIRE<66
44 PREDICTABILITY OF BRACHIORADIALIS REFLEX TESTING Subpopulation on No MedicationNormalsHypothyroid (+)Euthyroid(-)RestingMetabolicRate> 2000 kcals.11758Brachio-RadialisReflexFire-Prefire< 66 msecs.12357
45 PREDICTABILITY OF BRACHIORADIALIS REFLEX TESTING Gold StandardRMR (+)RMR (-)BR Test (+)True Positives(117)False Positives(6)BR Test (-)False Negatives(1)True Negatives(58)
46 SENSITIVITYSensitivity is the proportion of those that are hypothyroid that are correctly diagnosed.It is expressed as:________True Positives_______ = __117__ = 0.992True Positives + False Negatives
47 SPECIFICITYSpecificity is the proportion of those that are euthyroid that were correctly identified.It is expressed as:________True Negatives_______ = ___58___ = 0.906True Negatives + False Positives
48 PREDICTIVE VALUE of POSITIVE TEST Predictive Value of a Positive Test is the proportion of those with a positive test that are hypothyroid.It is expressed as:________True Positives_______ = ___117__=True positives + False Positives
49 PREDICTIVE VALUE of NEGATIVE TEST Predictive Value of a Negative Test is considered the proportion of those with a negative test who are euthyroid:It is expressed as:_______True Negatives_______ = ___58____=False Negatives + True Negatives
50 HOW TO OPTIMIZE THYROID ACTIVITY AND TREATMENT WHAT TO DOWHAT TO AVOIDDIETCAL/DAYORGANIC PALEOLITHIC FOODSIRON RICH FOODSLOW CALORIE, LOW FAT DIETSSKIPPING MEALSINDUSTRIALIZED FOODSALCOHOL, VINEGAR CAFFEINEEXCESS ANIMAL PROTEINFIBER RICH CEREALSSLEEPSLEEP SUFFICIENTLY6-9 HRS/NIGHTSLEEP DEPRIVATIONSTRESSSOME STRESS MANAGEMENTTECHNIQUEPROLONGED STRESSEXCESSIVE PHYSICAL ACTIVITYHERTOGHE, T; The Hormone Handbook. International Medical BooksSurrey, UK, 2006, p87.
77 ANTIBODIES NOT RECOGNIZING HASHIMOTO’S AND TSHANTIBODIES NOT RECOGNIZING(BINDING) NEW MEDANTIBODIES STILL HIGH30 DAYS AFTER
78 THYROID EFFECTS ON SERUM LIPIDS SIMILAR TO A STATIN DRUGN=30
79 ADAPTING THYROID DOSE TO ENVIRONMENT INCREASE DOSE(5-20% MORE)LOWER DOSE(5-20% LESS)CONDITIONSINSUFFICIENT EFFECTSWINTERIN THE MOUNTAINSEXERCISING A LOTHIGH PROTEIN DIETLOW VEGGIE/FRUIT DIETLOW CALORIE DIETBETA BLOCKERSORAL ESTROGENSLEEP DEPRIVATIONSITUATIONS REQUIRING MENTAL ALERTNESSEXCESSIVE EFFECTSSUMMERAT THE BEACHEXCESSIVE STRESSLOW PROTEIN DIETHIGH VEGGIE/FRUIT DIETCAFFEINATED DRINKSUNTREATED CORTISOL DEFICIENCYANDROGENS IN WOMENGROWTH HORMONE TREATMENTINSULIN TREATMENTHERTOGHE, T; The Hormone Handbook. International Medical BooksSurrey, UK, 2006, p89.
80 Combination Therapy $82.60 for 30 day supply COST OF THYROID MEDSPHARMACY30 day supplyARMOUR120 mgSYNTHROID200 mcgCYTOMEL50 mcgWALGREENS$13.79$28.19$46.49OSCO$21.69$39.00$75.00K-MART$15.97$29.69$48.97COSTCO$10.19$21.17$41.89AVERAGE$15.41$29.51$53.09Many on synthetic thyroid require both T3 and T4Combination Therapy $82.60 for 30 day supply
81 THYROID MYTHS DOES SUBCLINCAL HYPOTHYROID NEED TO BE TREATED ? HEALTH RISK IS HUGE IF UNTREATEDIS TSH THE BEST CLINICAL MARKER ?INSENSITIVE NEAR NORMALGETS TOO SMALL BEFORE FULL CLINICAL EFFECTRECEPTOR ACTIVITY DOESN’T REFLECT METABOLIC DEMANDIS IODINE GOOD FOR THYROID FUNCTION ?DECREASES THYROID FUNCTION IF NOT DEFICIENTARE SYNTHETIC THYROID MEDS MORE PRECISE AND MORE SCIENTIFIC THAN NATURAL ?NATURAL THYROID IS BIOIDENTICAL, U.S.P. AND HAS > EFFECTHALF-LIFE IS LONG IN MOST THYROID MEDSMOST PEOPLE END UP ON 2 SYNTHETIC MEDSIF SYNTHROID ALONE CAN’T CONVERT T4 TO T3IF CYTOMEL ALONE T4 GOES TO ZERO