Endocrinology Review: Thyroid, Insulin, and Hormones, Slides of Medicine

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Boards and Beyond: Endocrinology A Companion Book to the Boards and Beyond Website Jason Ryan, MD, MPH Version Date: 7-8-

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Thyroid Anatomy

• Two lobes (left, right)
• Isthmus: thin band of tissue between lobes
• Sometimes pyramidal lobe above isthmus Thyroid Gland Jason Ryan, MD, MPH Thyroid Anatomy
• Blood supply: superior and inferior thyroid arteries
• Superior thyroid: 1st branch external carotid artery
• Inferior thyroid: Thyrocervical trunk (off subclavian) Thyroid Embryology
• Forms from floor of pharynx (epithelial cells) Thyroid Embryology
• Descends into neck
• Initially maintains connection to tongue
• Thyroglossal duct
• Disappears later in development
• Two remnants of duct in child/adult
• Foramen cecum in tongue
• Pyramidal lobe of thyroid Thyroglossal Duct Cyst
• Persistent remnant of thyroglossal duct
• Midline neck mass ; usually painless
• Usually discovered in childhood
• Classically, move up with swallowing or tongue protrusion
• May contain thyroid cells

Hormone Synthesis Oxidation Follicular Cell Iodide Thyroid Peroxidase (TPO) (^) Ty Ty (^) Ty Ty I 2 Ty Plasma

TG

Follicle Lumen Hormone Synthesis Iodineuptake NIS Na-Iodine Symporter Follicular Cell Perchlorate (ClO4-) Pertechnetate (TcO4-) Na Iodide (^) X NIS Ty^ Ty^ Ty^ Ty^ Ty Plasma

TG

Follicle Lumen Hormone Synthesis Organification Monoiodotyrosine Tyrosine^ (MIT)

Thyroid Peroxidase (TPO)

Iodine (I 2 )

Diiodotyrosine (DIT) Hormone Synthesis CouplingReactions Thyroid Peroxidase (TPO) Monoiodotyrosine (MIT) Triiodothyronine ( T 3 ) Diiodotyrosine (DIT) Hormone Synthesis CouplingReactions Diiodotyrosine (DIT) Thyroid Peroxidase (TPO) Thyroxine ( T 4 ) Diiodotyrosine (DIT) TPO ThyroidPeroxidase

• Multifunctional enzyme
• Catalyzes:
  • Oxidation of iodide
  • Organification of iodine into MIT/DIT
  • Coupling of MIT/DIT into T3/T
• TPO antibodies common in autoimmune thyroid disease

Hormone Synthesis Plasma T3 T3^ T4^ Follicle^ Lumen Follicular Cell (^) T T4 (^) T Proteolysis TG TPO Iodide MIT^ DIT^ MITDIT Thyroid Peroxidase (TPO) TPO TG I 2 Ty^ Ty^ Ty^ Ty^ Ty TG Thyroid Hormones

• T4 is major hormone produced by thyroid gland

  • 90% of thyroid hormone produced is T

• T3 more potent hormone
• T4 is a “prohormone” for T
• 5’ deiodinase converts T4  T
• Most conversion occurs in peripheral tissues Iodine 5’-deiodinase Thyroxine ( T 4 ) (^) Triiodothyronine ( T 3 ) T3 T4^ T4^ T Hyperthyroid Medications
• Propylthiouracil (PTU)
• Inhibits TPO: ↓ T3/T4 from thyroid gland
• Inhibits 5’-deiodinase: ↓ T4 to T3 conversion peripherally
• Methimazole
• Inhibits TPO
• Propranolol
• Beta blocker
• Weak inhibitor of 5’-deiodinase
• Excellent drug in thyrotoxicosis PTU and Methimazole are both “thioamides”
• Blocks catecholamines and T4-T3 conversion Wolff-Chaikoff Effect
• Excessive iodide in diet could lead to hyperthyroidism
• Thyroid protects itself via Wolff-Chaikoff Effect
• Organification inhibited by ↑ iodide
• Less synthesis of MIT/DIT Amiodarone
• Class III antiarrhythmic drug
• Commonly used in atrial fibrillation
• Contains iodine
• Can cause hypothyroidism via excess iodine
• Wolff-Chaikoff Effect Amiodarone
• Mimics T
• Inhibits 5’-deiodinase
• ↓T3  ↑TSH from pituitary gland
• TSH rises after start of therapy then normalizes

Thyroid Hormone MetabolicEffects

• ↑ basal metabolic rate
  • Basal rate of energy use per time
  • Amount of energy burned if you slept all day
• ↑ Na/K ATPase pumps
  • More pumps = more ATP consumed
  • ↑ oxygen demand to replenish ATP
  • ↑ respiratory rate
  • ↑ body temperature
• Hyperthyroid patients: weight loss McDonough AA, et al. mRNA levels in kidney. Thyroid hormone coordinately regulates Na+ Am J Physiol. 1988 Feb;254(2 Pt 1):C323-9. - K+-ATPase alpha- and beta-subunit Thyroid Hormone MetabolicEffects
• ↑ Carbohydrate Metabolism
• ↑ glycogenolysis, gluconeogenesis
• ↑ Fat Metabolism
• ↑ lipolysis
• ↓ concentrations of cholesterol, triglycerides
• ↑ low-density lipoprotein receptors in liver (↓ LDL)
• ↑ cholesterol secretion in bile
• Hypothyroid patients: ↑ cholesterol
• Hyperthyroid patients: hyperglycemia Thyroid Hormone CardiacEffects
• ↑ CO/HR/SV/contractility
• ↑ β1 receptors in heart
• Hyperthyroid patients: Tachycardia Thyroid Hormone CNSand Boneeffects
• TH required for normal bone growth/CNS maturation
• Childhood hypothyroidism  cretinism
• Stunted growth
• Mental retardation
• Causes
• Iodine deficiency (3rd^ world)
• Thyroid dysgenesis
• Inborn errors of hormone synthesis (dyshormonogenesis)
• TPO most common Thyroid Hormone CNSand Boneeffects
• Most common treatable cause of mental retardation
• Most babies appear normal
• Maternal T3/T4 crosses placenta
• Newborn screening programs
• Measure T4 or TSH from heel-stick blood specimens Thyroid Hormone CNSand Boneeffects
• Mental retardation
• Coarse facial features
• Short stature
• Umbilical hernia
• Enlarged tongue

Thyroid Hormone Regulation

• Serum T4/T3 level sensed by hypothalamus
• Releases thyroid releasing hormone (TRH) Thyroid Hormone Regulation
• TSH (thyrotropin) released by anterior pituitary
• Binds to receptors on follicular cells
• Activates cAMP/PKA 2nd^ messenger system
• ↑ T3/T4 release
• ↑ rate of proteolysis of thyroglobulin
• Leads to rapid release of more T3/T
• Also stimulates thyroid cell growth, TG synthesis Pregnancy
• Multiple effects on thyroid hormone production
• Rise in total plasma T4/T3 levels
• Rise in TBG levels (estrogen)
• hCG stimulates thyroid (same alpha unit as TSH)
• Raises free T4  lower TSH TBG Total T TSH Free T Weeks of Pregnancy Thyroid Panel
• Four standard measurements to assess thyroid Note: T4 > T Total T4 >> Free T (most bound to TBG) Calcitonin
• Hormone produced by thyroid
• Synthesized by parafollicular cells (C-cells) Calcitonin
• Lowers serum calcium
• Suppresses resorption of bone; inhibits osteoclasts
• Inhibits renal reabsorption of calcium, phosphorus
• Increased calcium in urine
• Probably minor role in calcium handling in humans
• Used as pharmacologic therapy for hypercalcemia

Hyperthyroidism

• Metabolism SPEEDS UP
• Hyperactivity
• Heat intolerance
• Weight loss with increased appetite
• Diarrhea
• Hyperreflexia
• Warm, moist skin
• Fine hair
• Tachycardia (atrial fibrillation) Thyroid Replacement
• Levothyroxine (Synthroid): synthetic T
• Liothyronine (Cytomel): synthetic T
• Levothyroxine preferred
• T3 absorbed from intestines rapidly
• Can cause mild hyperthyroidism symptoms
• Tachycardia, tremor
• Also, T4 converted to T
• Titrate dose until TSH is normal Thyroid Storm
• Life-threatening hyperthyroidism (thyrotoxicosis)
• Usually precipitated by acute event
• Patient with pre-existing hyperthyroid disease
• Grave’s or toxic multinodular goiter
• Surgery, trauma, infection
• Massive catecholamine surge
• Fever, delirium
• Tachycardia with death from arrhythmia
• Hyperglycemia (catecholamines/thyroid hormone)
• Hypercalcemia (bone turnover) Goiter
• Enlarged thyroid
• High TSH, inability to produce T3/T
• Thyroid stimulating antibodies (Grave’s) Lab Findings
• Best initial test is TSH

TSH

Lab Findings

• Most disorders are primary disease
  • Disorder of the thyroid gland
  • TSH is opposite thyroid hormone
  • Hypothyroidism = ↑ TSH with low T3/T
  • Hyperthyroidism = ↓ TSH with high T3/T

Reverse T

• Isomer of T3 also derived from T Revere T Thyroxine ( T 4 ) Triiodothyronine ( T 3 ) Lab Findings
• Central hyper/hypo thyroid disease
• Low TSH and low T3/T4; High TSH and high T3/T
• Rare disorders of the pituitary, hypothalamus
• Usually hypothalamic-pituitary tumors
• Tumors block secretion TRH/TSH (hypothyroidism)
• Rarely a TSHoma can secrete TSH (hyperthyroidism)
• Pituitary resistance to thyroid hormone (hyperthyroidism) Reverse T
• Level usually parallels T
• Low T4  Low rT
• One special use: Euthyroid sick syndrome
• Critically ill patients  low TSH  Low T3/T
• Can look like central hypothyroidism
• rT3 rises in critical illness (impaired clearance)
• Critically ill patient with low TSH/T4/T
• Check rT
• Low  central hypothyroidism
• High  sick euthyroid syndrome Hyperthyroidism
• Grave’s disease (#1 cause)
• Toxic multinodular goiter
• Amiodarone
• Iodine load
• Early thyroiditis Grave’s Disease
• Autoimmune disease
• Thyroid stimulating antibodies produced
• Symptoms of hyperthyroidism occur Grave’s Disease
• Exophthalmos (bulging eyes)
• Proptosis (protrusion of eye) and periorbital edema
• Usually no ocular symptoms
• Pretibial myxedema (shins)
• T-cell lymphocyte activation of fibroblasts
• Fibroblasts contain TSH receptor
• Stimulation  secretion of glycosaminoglycans
• Hydrophilic substances, mostly hyaluronic acid
• Draws in water  swelling

Radioactive Iodine Uptake

• Important test for thyroid nodules
• Administration of I^131 (lower dose than ablation)
• Contraindicated in pregnancy/breast feeding
• “Hot” nodule
  • Takes up I^131
  • Not-cancerous
• “Cold” nodule
  • Chance of cancer (~5%)
  • Often biopsied (Fine-needle aspiration) Toxic Adenomas
• Nodules in thyroid that function independently
• Usually contain mutated TSH receptor
• Do not respond to TSH
• One nodule: Toxic adenoma
• Multiple: Toxic multinodular goiter
• Findings:
• Palpable nodule
• Hyperthyroidism symptoms/labs
• Treatment: Radioactive iodine or surgery Jod-Basedow Phenomenon
• Iodine-induced hyperthyroidism
• Often occurs in regions of iodine deficiency
• Introduction of iodine  hyperthyroidism
• Often occurs in patients with toxic adenomas
• Drugs administered with high iodine content
• Expectorants (potassium iodide)
• CT contrast dye
• Amiodarone Amiodarone
• Two types of hyperthyroidism
• Type I
• Occurs in patients with pre-existing thyroid disease
• Grave’s or Multi-nodular goiter
• Amiodarone provides iodine  excess hormone production
• Type II
• Destructive thyroiditis
• Excess release T4/ T3 (no ↑ hormone synthesis)
• Direct toxic effect of drug
• Can occur in patients without pre-existing thyroid illness Hypothyroidism
• Iodine deficiency
• Iodine excess
• Congenital hypothyroidism
• Amiodarone
• Thyroiditis
• Hashimoto’s (#1 cause when dietary iodine is sufficient)
• Subacute
• Riedel’s Iodine Deficiency
• “Endemic goiter”
• Goiter in region with widespread iodine deficiency
• Common in mountainous areas (iodine depleted by run-off)
• Constant elevation of TSH  enlarged thyroid

Iodine

Iodine

Deficiency Excess Load

Hypothyroidism Hypothyroidism (^) Hyperthyroidism Goiter Wolff-Chaikoff Iodine Excess

• Excessive iodide in diet could lead to hyperthyroidism
• Thyroid protects itself via Wolff-Chaikoff Effect
• Organification inhibited by ↑ iodide
  • Less synthesis of MIT/DIT
• Chronic, high iodine intake  goiter/hypothyroidism Goitrogens
• Substances that inhibit thyroid hormone production
• Most common is iodine
• Lithium (inhibits release of thyroid hormone)
• Certain foods (cassava and millet) Amiodarone
• 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”
• Also mimics T
• Inhibits 5’-diodinase Amiodarone Always check TSH before starting amiodarone

Amiodarone

Hypothyroidism (^) Hyperthyroidism Iodine Excess (^) 5’- Inhibits diodinase Iodine Load^ Thyroiditis Hypothyroidism (^) Hypothyroidism Wolff-Chaikoff (^) ↓T4T Congenital Hypothyroidism

• TH required for normal bone growth/CNS maturation
• Childhood hypothyroidism  cretinism
  • Stunted growth
  • Mental retardation
• Causes
  • Iodine deficiency (3rd^ world)
  • Thyroid dysgenesis
  • Inborn errors of hormone synthesis (dyshormonogenesis)
  • TPO most common

Riedel’s Thyroiditis

• Fibroblast activation/proliferation
• Fibrous tissue (collagen) deposition in thyroid
• “Rock hard” thyroid
• Often extends beyond the thyroid
  • Parathyroid glands  hypoparathyroidism
  • Recurrent laryngeal nerves  hoarseness
  • Trachea compression  difficulty breathing
• Associated with IgG4 plasma cells
  • May be an “IgG4-related disease” (autoimmune pancreatitis)
  • IgG4 plasma cells identified in biopsy specimens Subacute Thyroiditis de Quervain’s/granulomatousthyroiditis
• Granulomatous inflammation of thyroid
• Occurs in young females
• Tender , enlarged thyroid gland
• Hyperthyroid  euthyroid  hypothyroid
• Treatment:
• Anti-inflammatories (aspirin, NSAIDs, steroids)
• Thyroid symptoms usually mild (no treatment)
• Usually resolves in few weeks Lymphocytic Thyroiditis PainlessThyroiditis
• Variant of Hashimoto’s
• Lymphocytic infiltration of thyroid gland
• Transient hyperthyroidism
• Can look like Grave’s without eye/skin findings
• Serum thyroid stimulating immunoglobulins not elevated
• Followed sometimes by hypothyroidism
• Can look like Hashimoto’s
• Usually self-limited (weeks)

General Principles

• Thyroid cancer usually no hyper/hypo symptoms
• Often presents as nodule
• Differential is benign adenoma versus cancer
• Biopsy done by fine needle aspiration Thyroid Cancer Jason Ryan, MD, MPH Thyroid Imaging
• Ultrasound
• Some characteristics suggest cancer
• Borders, vascularity, calcifications Radioactive Iodine Uptake
• Small oral dose I^131 given to patient
• Scintillation camera  image of thyroid
• Normal: diffuse, even uptake
• Diffuse high uptake: Grave’s
• Diffuse low uptake: Hashimoto’s
• Multiple areas of high uptake: nodular goiter
• Single “hot” nodule: adenoma
• Single “cold” nodule: Possible cancer
• Most cancers do not make hormone
• About 10% cold nodules are malignant Follicular Adenoma
• Common cause of thyroid nodules
• Benign proliferation of follicles
• Normal follicular tissue seen on biopsy
• Completely surrounded by fibrous capsule
• FNA 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  surgery Thyroid Cancer
• Papillary
• Follicular
• Medullary
• Anaplastic