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Lab FindingsLab Findings Best initial test is TSH Most disorders are primary disease TSHLab FindingsReverse T3 Central hyper/hypo thyroid disease Disorder of the thyroid glandTSH is opposite thyroid hormoneHypothyroidism TSH with low T3/T4Hyperthyroidism TSH with high T3/T4 Isomer of T3 also derived from T4Low TSH and low T3/T4; High TSH and high T3/T4Rare disorders of the pituitary, hypothalamusUsually hypothalamic-pituitary tumorsTumors block secretion TRH/TSH (hypothyroidism)Rarely a TSHoma can secrete TSH (hyperthyroidism)Pituitary resistance to thyroid hormone (hyperthyroidism)Reverse T3Thyroxine (T4)Triiodothyronine (T3)Reverse T3Hyperthyroidism Level usually parallels T4 Low T4 Low rT3 One special use: Euthyroid sick syndrome Critically ill patients low TSH Low T3/T4 Can look like central hypothyroidism rT3 rises in critical illness (impaired clearance) Critically ill patient with low TSH/T4/T3 Check rT3 Low central hypothyroidism High sick euthyroid syndrome11Graves' disease (#1 cause)Toxic multinodular goiterAmiodaroneIodine loadEarly thyroiditis

Graves' DiseaseGraves' Disease Autoimmune disease Thyroid stimulating antibodies produced Symptoms of hyperthyroidism occur Exophthalmos (bulging eyes) Proptosis (protrusion of eye) and periorbital edema Usually no ocular symptomsPretibial myxedema (shins)T-cell lymphocyte activation of fibroblastsFibroblasts contain TSH receptorStimulation secretion of glycosaminoglycans Hydrophilic substances, mostly hyaluronic acid Draws in water swellingGraves' DiseaseGraves' Disease Diagnosis: Usually hyperthyroid labs plus exophthalmos Can measure TSH receptor antibodies “Thyroid stimulating immunoglobulins” TreatmentJonathan Trobe, M.D./Wikipedia Symptoms: beta blockers, thionamides Drugs often started in preparation for definitive therapy Radioactive iodine ablation or surgeryHerbert L. Fred, MD and Hendrik A. van DijkThionamidesThionamides Methimazole Skin rash (common) Agranulocytosis Inhibits thyroid peroxidase (TPO) Organification of iodine Coupling of MIT/DIT Propylthiouracil (PTU) Inhibits TPO Also inhibits 5’-deiodinase Blunts peripheral conversion T4 T3Rare drop in WBCMay present as fever, infection after starting drugWBC improves with stopping drugAplastic anemia cases reported Hepatotoxicity12

Thyroid StormThionamidesTreatment Methimazole: teratogen Propranolol Associated with congenital malformations Especially 1st trimester PTU often used during early pregnancy Beta blocker Blocks T4 T3 conversion Thionamides (PTU, Methimazole) SSKI (saturated solution of potassium iodide) Iodide load shuts down T4 production Wolff-Chaikoff effect Steroids Reduce T4 T3 conversion Suppress auto-immune damage Treat possible concomitant adrenal insufficiencyGraves' Ophthalmopathy Toxic Adenomas Nodules in thyroid that function independentlySometimes worsens despite treating hyperthyroidismCan cause irritation, excessive tearing , painSymptoms often worse by cold air, wind, bright lightsSevere inflammation treatments: Steroids Radiation SurgeryUsually contain mutated TSH receptorDo not respond to TSHOne nodule: Toxic adenomaMultiple: Toxic multinodular goiter Findings: Palpable nodule Hyperthyroidism symptoms/labs Treatment: Radioactive iodine or surgeryJonathan Trobe, M.D./WikipediaJod-Basedow PhenomenonRadioactive Iodine Uptake Iodine-induced hyperthyroidism Often occurs in regions of iodine deficiencyImportant test for thyroid nodulesAdministration of I131 (lower dose than ablation)Contraindicated in pregnancy/breast feeding“Hot” nodule Introduction of iodine hyperthyroidism Often occurs in patients with toxic adenomas Takes up I131 Not-cancerous “Cold” nodule Chance of cancer ( 5%) Often biopsied (Fine-needle aspiration)13Drugs administered with high iodine contentExpectorants (potassium iodide)CT contrast dyeAmiodarone

AmiodaroneHypothyroidism Two types of hyperthyroidism Type I Occurs in patients with pre-existing thyroid disease Graves' or Multi-nodular goiter Amiodarone provides iodine excess hormone production Type II Iodine deficiencyIodine excessCongenital hypothyroidismAmiodaroneThyroiditis Hashimoto’s (#1 cause when dietary iodine is sufficient) Subacute Riedel’sDestructive thyroiditisExcess release T4/ T3 (no hormone synthesis)Direct toxic effect of drugCan occur in patients without pre-existing thyroid illnessIodine DeficiencyIodine Excess “Endemic goiter” Excessive iodide in diet could lead to hyperthyroidism Thyroid protects itself via Wolff-Chaikoff Effect Organification inhibited by iodide Goiter in region with widespread iodine deficiency Common in mountainous areas (iodine depleted by run-off) Constant elevation of TSH enlarged thyroid Less synthesis of MIT/DIT Chronic, high iodine intake goiter/hypothyroidismWellcome ImagesIodineDeficiencyIodineExcessHypothyroidism HypothyroidismWolff-ChaikoffGoiterGoitrogens LoadHyperthyroidism14Substances that inhibit thyroid hormone productionMost common is iodineLithium (inhibits release of thyroid hormone)Certain foods (cassava and millet)

AmiodaroneAmiodarone Can cause hypothyroidism Excess iodine Wolff-Chaikoff Effect Suppression of thyroid hormone synthesis Normal patients “escape” in few weeks Pre-existing subclinical thyroid disease “failure to escape”Hypothyroidism Also mimics T4Iodine Excess Inhibits 5’-diodinaseHypothyroidismWolff-ChaikoffIodine LoadThyroiditisHypothyroidism T4 T3CNS and Bone effects Most common treatable cause intellectual disability Newborn screening programs TH required for normal bone growth/CNS maturation Childhood hypothyroidism cretinism Stunted growth Intellectual impairment Measure T4 or TSH from heel-stick blood specimens CausesIodine deficiencyThyroid dysgenesisInborn errors of hormone synthesis (dyshormonogenesis)TPO most commonThyroid HormoneIatrogenic HypothyroidismCNS and Bone effects Inhibits5’-diodinaseHyperthyroidismThyroid HormoneCongenital Hypothyroidism AmiodaroneAlways check TSHbefore startingamiodarone Thyroid surgeryIntellectual impairmentCoarse facial featuresShort statureUmbilical herniaEnlarged tongue Often done for Graves' or malignancy Radioiodine therapy I131 administered orally as solution or capsuleBeta-emissions tissue damageAblation of thyroid function over weeksDone for Graves' or malignancy Neck radiation Hodgkin’s lymphoma Head and neck cancerWellcome Images/Wikipedia15

Hashimoto’s ThyroiditisHashimoto’s ThyroiditisChronic Autoimmune ThyroiditisChronic Autoimmune Thyroiditis Most common cause of hypothyroidism (non-diet) Lymphocytes infiltrate thyroid gland Antibodies produced Anti-TPO Anti-thyroglobulin Autoimmune disorder (T-cell attack thyroid; B cell activation) HLA-DR3, HLA-DR5 and others Histology: Massive lymphocytic infiltrate (germinal centers) Hurthle cells (enlarged eosinophilic follicular cells)Hashimoto’s ThyroiditisSubacute ThyroiditisChronic Autoimmune Thyroiditis de Quervain’s/granulomatous thyroiditis Primarily occurs in womenEnlarged non-tender thyroid glandGradual loss of thyroid function symptomsSymptoms/labs of hypothyroidismTreatment: thyroid hormone replacementIncreased risk of Non Hodgkin B cell lymphoma Anti-inflammatories (aspirin, NSAIDs, steroids) Thyroid symptoms usually mild (no treatment) Usually resolves in few weeksLymphocytic ThyroiditisRiedel’s Thyroiditis Granulomatous inflammation of thyroidOccurs in young femalesTender, enlarged thyroid glandHyperthyroid euthyroid hypothyroidTreatment:Painless Thyroiditis Variant of Hashimoto’s Lymphocytic infiltration of thyroid gland Transient hyperthyroidismFibroblast activation/proliferationFibrous tissue (collagen) deposition in thyroid“Rock hard” thyroidOften extends beyond the thyroid Can look like Graves' without eye/skin findings Serum thyroid stimulating immunoglobulins not elevated Parathyroid glands hypoparathyroidism Recurrent laryngeal nerves hoarseness Trachea compression difficulty breathing Followed sometimes by hypothyroidism Can look like Hashimoto’s Associated with IgG4 plasma cells Usually self-limited (weeks) May be an “IgG4-related disease” (autoimmune pancreatitis) IgG4 plasma cells identified in biopsy specimens16

Thyroid CancerGeneral Principles Thyroid CancerThyroid cancer usually no hyper/hypo symptomsOften presents as noduleDifferential is benign adenoma versus cancerBiopsy done by fine needle aspirationJason Ryan, MD, MPHThyroid ImagingRadioactive Iodine Uptake Ultrasound Some characteristics suggest cancer Borders, vascularity, calcifications Most cancers do not make hormone About 10% cold nodules are malignantNevit Dilmen/WikipediaFollicular Adenoma Small oral dose I131 given to patientScintillation camera image of thyroidNormal: diffuse, even uptakeDiffuse high uptake: Graves'Diffuse low uptake: Hashimoto’sMultiple areas of high uptake: nodular goiterSingle “hot” nodule: adenomaSingle “cold” nodule: Possible cancerThyroid Cancer Common cause of thyroid nodulesBenign proliferation of folliclesNormal follicular tissue seen on biopsyCompletely surrounded by fibrous capsuleFNA cannot distinguish between adenomas/cancer Cannot see entire capsule Follicular carcinoma has similar histology by FNA FNA follicular pathology followed over time Growth, suspicious new findings han /Wikipedia

Papillary CarcinomaPapillary Carcinoma Most common form thyroid cancer ( 80%) Increased risk with prior radiation exposure Childhood chest radiation for mediastinal malignancy or acne Survivors of atomic bomb detonation (Japan) Nuclear power plant accidents (Chernobyl) Presents as thyroid nodule Sometimes seen on chest/neck imaging (CT/MRI) Diagnosis made after fine needle aspiration (FNA) Excellent prognosis Treated with surgery plus radioactive iodine ablationKGH/WikipediaPapillary CarcinomaPsammoma Bodies Three key pathology findings: Calcifications with an layered pattern Seen in other neoplasms but only papillary for thyroid Psammoma bodies Nuclear grooves Orphan Annie’s Eye Nuclei Diagnosis made by nuclear findingsWikipedia/Public DomainNuclear GroovesOrphan Annie's Eyes Empty-appearing nucleiKGH/WikipediaWhite clearingKGH/Wikipedia18William Creswell/Flikr

Follicular Carcinoma Follicular Carcinoma Possible hematogenous metastasis Treatment:Similar to follicular adenomaBreaks through (“invades”) fibrous capsuleFNA cannot distinguish between adenomas/cancerFollicular pathology followed over time Thyroidectomy I131 to ablate any remaining tissue or metastasis Growth, suspicious new findings surgeryYale Rosen/WikipediaMedullary CarcinomaMedullary Carcinoma Cancer of parafollicular cells (C cells) Produces calcitoninMalignant cells/Amyloid “stroma” Lowers serum calcium Normally minimal effect on calcium levels Used for monitoring Amyloid deposits in thyroid Amyloid protein deposits Calcitonin peptide Appearance of amyloid on biopsyNephron/WikipediaMEN SyndromesAnaplastic CarcinomaMultiple Endocrine NeoplasiaUndifferentiated Carcinoma Occurs in elderly Highly malignant - invades local tissues Gene mutations that run in families Cause multiple endocrine tumors MEN 2A and 2B associated with medullary carcinoma Caused by RET oncogene mutation Some patients have elective thyroidectomyDysphagia (esophagus)Hoarseness (recurrent laryngeal nerve)Dyspnea (trachea)Don’t confuse with Riedel’s (“rock hard” thyroid/young pt) Poor prognosis Pathology: Undifferentiated cells No papilla, follicles, or amyloid19

Adrenal GlandsAdrenal Glands Located above kidneys Arteries: Suprarenal arteries Left and right Superior, inferior, middle Veins:Adrenal Glands Left adrenal renal vein IVC Right adrenal IVCJason Ryan, MD, MPHWikipedia /Public DomainCortex and MedullaSignal Transmission Cortex: Three groups of hormones Mineralocorticoids (aldosterone)Glucocorticoids (cortisol)Androgens (testosterone)Derived from mesoderm Medulla Epinephrine and norepinephrine Sympathetic nervous system control Derived from neural crestOpenStax College/WikipediaUse with permission, Katzung BG, Basic and Clinical Pharmacology, 10th ed. New York, McGraw Hill, 2007MineralocorticoidsCollecting DuctLumen (Urine) Most important is aldosterone Key effects on kidney function Release controlled by RAA systemAldosterone Renin-angiotensin-aldosterone Increase Na /Water resorption Promote K /H excretionAldosteroneCorticosteroneK Principal CellNa AldosteroneH2OIntercalated CellAldosterone11-deoxycorticosterone20H ATPNa K Interstitium/Blood

Adrenal AndrogensCortisol Small contribution to androgen production in males 50% androgens for females Clinical relevance: congenital adrenal hyperplasia Major glucocorticoid Synthesized by adrenal cortex Binds to intracellular receptors (cytosol) Glucocorticoid receptor (GR) Over/underproduction abnormal sexual development Production stimulated by ACTH (like cortisol)Dehydroepiandrosterone(DHEA)Testosterone Translocates to nucleus Activates/suppresses gene transcriptionAndrostenedionePituitary-Adrenal AxisCircadian Rhythms Controls cortisol secretion Hypothalamus: CRH Serum cortisol highest early morning (about 6 AM) 10 to 20 mcg/dL Lowest one hour after sleep onset Corticotropin releasing hormone Paraventricular nucleus (PVN) Less than 5 mcg/dL Anterior pituitary: ACTH Testing rarely done with single blood test Adrenocorticotropic hormone Acts on adrenal gland cAMP/PKA 2nd messenger Adrenal: CortisolCortisolDrosenbach/WikipediaCortisol Binding Globulin Cortisol poorly soluble in plasma Most ( 90%) serum cortisol bound to CBG Levels estrogenCortisolHormone Effects Maintains blood pressureCortisol Effects on vascular smooth muscle Increases vascular sensitivity (α1) to norepi/epi NO mediated vasodilationCortisol cortisol: hypertension (Cushing’s disease) cortisol: hypotension (adrenal insufficiency)21

CortisolHormone Effects Suppresses immune system Sequester lymphocytes in spleen/nodesCortisolCortisol Inactivate NF-KB Reduce T and B cell levels in plasma Block neutrophil migration peripheral neutrophil count Mast cells: blocks histamine release eosinophil counts Basis for steroids as immunosuppressive drug therapyCorticosteroid DrugsCortisolEffectsCortisol More glucose produced by liver synthesis of glucose 6-phosphatase, PEPCK eMethylprednisoloneBetamethasoneCortisolEffects Activation of lipolysis in adipocytes free fatty acids total cholesterol, triglyceridesKey inflammatory transcription factorMediates response to TNF-αControls synthesis inflammatory mediatorsCOX-2, PLA2, LipoxygenaseCortisolCortisol Less glucose taken up peripherally (muscle, fat) Net results: serum glucose More glycogen storage in liver synthesis of glycogen isol Enhanced effects of glucagon, epinephrine Leads to insulin resistance Long term steroid use: diabetes Stimulate adipocyte growth Key effect: fat deposition22Cortisol

CortisolEffectsZones of the Adrenal GlandsCortisol Muscle atrophy Skin effects Blunted epidermal cell division in skin collagen, inhibition of fibroblasts Net effects: Thin skin, easy bruising, striae Bones: Inhibits osteoblasts Steroids osteopenia and osteoporosisJpogi/Wikipedia /Public DomainZones of the Adrenal GlandsZona GlomerulosaProgesteronePregnenoloneCholesterol3-β hydroxysteroidDehydrogenase21-α hydroxylase11-β hydroxylaseAldosteroneZona GlomerulosaPregnenoloneCholesterolAngiotensin II xycorticosteroneCorticosteroneZona Glomerulosa3-β erol21-α hydroxylaseDesmolase PregnenoloneAngiotensin II AldosteroneSynthase11-β icosterone3-β hydroxysteroidDehydrogenaseProgesterone21-α hydroxylase11-β hydroxylase11-deoxycorticosterone

Zona GlomerulosaPregnenoloneZona FasciculataProgesterone17-α hydroxylase3-β ikipedia /Public Domain17-HydroxypregnenoloneZona FasciculataZona ReticularisCortisol17-Hydroxyprogesterone21-α hydroxylase11-β 7, 20 lyase3-β DHEA)AndrostenedioneTestosteroneMatthew Colo/WikipediaKetoconazole Antifungal Blocks ergosterol synthesis in fungi Potent inhibitor of 17,20 lyase androstenedione/testosterone Key side effect: gynecomastia Also inhibits 17-alpha hydroxylase, desmolase Blocks cortisol synthesis Can be used to treat Cushing’s syndrome24

CAHCongenitalAdrenal HyperplasiaCAHCongenital Adrenal Hyperplasia Enzyme deficiency syndrome Loss of one of the four enzymes for cortisol synthesis 21-α hydroxylase11-β hydroxylase17-α hydroxylase3-β hydroxysteroid dehydrogenaseJason Ryan, MD, MPHCAHCongenital Adrenal HyperplasiaACTHAldosteroneMatthew Colo/WikipediaCAHLow CortisolCongenital Adrenal HyperplasiaSigns/Symptoms All result in low cortisol Stimulates ACTH release Can cause production of other hormones Hypoglycemia Nausea/vomiting Mineralocorticoids Androgens Cortisol ACTHAdrenalHyperplasia Non-cortisolhormone synthesis25CholesterolCortisolAndrogens page

This book of slides is intended as a companion to the videos for . Measure T4 or TSH from heel -stick blood specimens Thyroid Hormone CNS and Bone effects . Cold intolerance Weight gain with