Thyroid Gland
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Thyroid Gland • Largest endocrine gland • Devoted only to endocrine function • Oldest gland phylogenically – All vertebrates, many invertebrates Thyroid Hormones: Evolution •T4 and T3: Same in all vertebrates from land mammals to teleosts • TSH: Trophic and secretion • Each tissue regulates its thyroid status • Important for metamorphosis and development – Amphibian and frog metamorphosis – Eye opening in rats (day 10) – CNS development in mammals (cretins) NIS IHC: 2 mo. old Mouse Berlin 2017 Thomas Rosol 1 Endocytosis of Colloid NIS IHC: 9 mo. old Mouse Thyroid Hormone Deiodination Activation and Metabolism Thyroid Hormone Deiodination 3’ 3 • Deiodinase I (liver, kidney) – T4 to T3 or rT3 to T2 * 5’ 5 • (5’)-Deiodinase II (thyroid, heart, CNS, fat, 3,5,3’,5’-T4 muscle) – Deiodinates the outer ring only – Major activating enzyme 3,5,3’-T 3 3,3’,5’-rT 3 – T4 to T3; rT3 to T2 • Deiodinase III (fetus, placenta) – T4 to rT3; T3 to T2 3,3’T2 Berlin 2017 Thomas Rosol 2 Thyroid Stimulating Hormone Short Term Response of Follicular Cells (TSH) To Increased TSH Secretion • Glycoprotein: Alpha & Beta subunits • Short (~15 minute) half-life • Circulates free (unbound) in blood • Highly species-specific – Human, primate, rat, & dog assays – Little cross reactivity – Male rats greater than females Long Term Response of Follicular Cells Replacement Therapy with Thyroxine To Increased TSH Secretion Thyroglossal Duct Cyst • Ventral Midline • Base of Tongue to Anterior Mediastinum • Thyroidogenic Epithelium in Wall • Colloid-Like Contents Berlin 2017 Thomas Rosol 3 Ultimobranchial Duct Cysts Cysts occur at the thyroid hilus; have a squamous epithelial lining; and accumulate keratin. Thyroid: Fetal Hypoplasia Guernsey, prolonged gestation Pathology of the Thyroid Gland Berlin 2017 Thomas Rosol 4 Ectopic Thyroid Parenchyma Ectopic Thyroid: Dog • Base of tongue to diaphragm • Species: Dog • Humans (10%) • Location – Usually sublingual, rare intracardiac – Along course of thyroglossal duct in cervical • Dogs (50%) region (>100%) – Intrapericardium, heart base – Intrathoracic (~50%) • Anterior mediastinum – Intracardiac; septum and right ventricle • Pericardium • Neoplasia more easily identifiable • Adventitia of the aorta • Primates (rare) • Significance • Rats and mice (rare) – Thyroidectomy is difficult – Neck, thorax, heart base – Can undergo hyperplasia or neoplasia Persistence of Thyroid Remnants at Base of Tongue (Foramen Caecum) Significance: Cysts Neoplasms Berlin 2017 Thomas Rosol 5 Lipofuscin Pigment • Accumulates in thyroid follicular cells with advancing age • Age-related color change to the thyroid gland – Young animals: Red – Aged animals: Dark brown THYROID ATROPHY • Trophic Atrophy – Subnormal TSH Production • Pituitary Neoplasm • Space-Occupying Cyst or Granuloma • Pressure Atrophy – Bilateral Lesions Adjacent to Thyroid • Cervical Cyst • Abscess • Neoplasm Berlin 2017 Thomas Rosol 6 Colloid Involution COMMON CAUSES Thyroid Gland HYPOTHYROIDISM IN DOGS • Atrophy of Follicular Cells – Low Cuboidal • LYMPHOCYTIC • FOLLICULAR THYROIDITIS ATROPHY • Decreased TSH-Mediated Endocytosis of Colloid Immune-Mediated Idiopathic • Distention of Follicles with Colloid ~50% ~50% – Macrofollicles DDx: Sick Euthyroid Syndrome Sick Euthyroid Syndrome • Overdiagnosis of hypothyroidism in critical illness • Decreased conversion of T4 to T3 –↓ T3 and ↑ reverse T3 – Normal or ↓ T4 – Normal or ↓ TSH • Changes in binding of thyroid hormones to serum proteins TSH IRMA for Dogs •TSH: subunits are unique • TSH levels are low in dogs compared to humans • False negative rate – up to one third • False positive rate – 10-20 percent • Combine with ultrasonography • Alternative: TSH stimulation test – Bovine pituitary extract (Sigma) not available due to Mad Cow Disease and development of human recombinant TSH (Thyrogen, Genzyme) Berlin 2017 Thomas Rosol 7 IDIOPATHIC THYROID ATROPHY “FOLLICULAR COLLAPSE” • Noninflammatory • Adipose Connective Degenerative Lesion Tissue Replacement Berlin 2017 Thomas Rosol 8 LYMPHOCYTIC THYROIDITIS (HASHIMOTO’S) • Species – Dog, chicken, laboratory rats – Non-human primates – Human beings • Thyroid antigens – Thyroglobulin – Thyroperoxidase (microsomal) – TSH receptor protein – Secondary antigens: colloid, nuclear, cytoskeletal proteins, tubulin IMMUNE-MEDIATED THYROIDITIS • Humoral immune response – Autoantibody production – Immune complexes along basement membrane – Proliferation of b-lymphocytes in thyroid • Cell-mediated immune response – Sensitized t-lymphocytes – Antibody-dependent cytotoxicity – Defective suppressor t-lymphocytes LYMYPHOCYTIC THYROIDITIS • ‘End stage’ • Interstitial fibrosis • Loss of thyroid follicles • Prominent C cells • Oncocytes (acidophilic cells with numerous mitochondria) Berlin 2017 Thomas Rosol 9 Hypothyroidism: Other Lesions Myxedema Immune-Mediated Diseases of the Endocrine System • Lymphocytic Thyroiditis (Hashimoto’s) • Lymphocytic Adrenalitis (Addison’s) • Lymphocytic Parathyroiditis • Juvenile-onset Diabetes Mellitus • Hypothalamic Diabetes Insipidus Berlin 2017 Thomas Rosol 10 Radiation-Induced Thyroiditis (131I, 125I) • Degeneration of Follicular Cells • Disruption of Thyroid Follicles • Thyroiditis SOURCES OF THYROID 131I Therapy in Cats RADIATION EXPOSURE TYPE SOURCE • Necrosis of parenchymal cells -Treatment of HyperTG with 131I INTENTIONAL -Diagnostic Scanning with 131I • Vascular damage or 123I – Thrombosis; hemorrhage -Radiotherapy of head and • Healing by fibrosis and collagen INADVERTANT neck cancer deposition -Atomic bomb blasts (Japan) • Loss of stem cells -Fallout (131I) from testing nuclear weapons -Laboratory Accidents ACCIDENTAL -Nuclear Reactor Accidents Histopathology Histopathology Berlin 2017 Thomas Rosol 11 IONIZING RADIATION ONLY KNOWN THYROID CARCINOGEN IN HUMANS THYROID CANCER IN CHILDREN CHERNOBYL NUCLEAR REACTOR ACCIDENT THYROID CARCINOMAS REPRESENT THE LARGEST NUMBER OF CANCERS OF ONE TYPE, CAUSED BY A SINGLE EVENT, ON ONE DATE, EVER RECORDED Reasons for High Incidence of Thyroid Cancer after Chernobyl Nuclear Reactor Accident • Greater Thyroid Exposure to Fallout Radioiodine – Milk is main route for Ingestion of Radioiodine • Intake: Children > Adults • Goat’s Milk has 10X more Iodine than Cow’s Milk – Uptake of Iodine is higher in Children • Thyroid Growth Occurs Primarily in Childhood – Sleeping Outdoors Increases Exposure Berlin 2017 Thomas Rosol 12 Goiter Hypertrophy and Hyperplasia of Follicular cells -Nonneoplastic -Noninflammatory Goiter Goiter • Ancient disease – Described for over 5000 years • Major human health problem • Historical interpretation • Predominantly due to iodine deficiency – Sign of beauty • Estimated over 200 million people affected – Punishment of gods – Adults • Iodine deficient regions – E.g., Great Lakes in USA Goiter: Causes • Deficient iodine intake – Deficient areas of the world – Mountainous regions; recent glaciation • Genetic enzyme defects – Congenital dyshormonogenetic goiter • Increased thyroxine demand Berlin 2017 Thomas Rosol 13 Goiter: Causes Amphibian Metamorphosis Assay • Goitrogenic chemicals • Detect substances that interact with – Block iodide trapping; NaI symporter hypothalamic-pituitary-axis during development – Conserved thyroid structure in vertebrates – Inhibit thyroperoxidase (TPO) with failure to oxidize iodide (I-) to I • Metamorphosis of Xenopus Laevis (African 2 Clawed Frog) tadpoles – Failure of fusion of colloid droplet and lysosomal bodies resulting in a failure to • Test for Endocrine Active Substances (EAS) release T4 and T3 • OECD (Org. Economic Co-operation & Development guidelines (www.oecd.org/dataoecd/44/52/40909207.pdf) Nieuwkoop and Faber (N&F) Stages • 21-day test – Hind limb length, development stage, thyroid histology • Nieuwkoop and Faber (N&F) staging – 45-49: First form tadpole – 49-56: Second form tadpole – 56-60+: Third form tadpole Control Perchlorate (62 ug/L) Diffuse Hyperplastic Goiter • Pathogenesis – TSH-mediated follicular cell stimulation • Compensatory mechanisms for iodine Perchlorate Perchlorate deficiency (62 ug/L) (250 ug/L) – Increase efficiency of iodine trapping by follicular cells; increased NIS – Preferential synthesis of T3 vs. T4 – TRH-TSH stimulation of follicular cell hypertrophy and hyperplasia with increased blood supply Grim, Tox. Pathol., 2009 Berlin 2017 Thomas Rosol 14 Diffuse Hyperplastic Goiter • Functional significance; species differences – Lambs • Poor wool development • Dome-like skull • Delayed skeletal maturation • Signs of mental deficiency – Retardation of brain growth; decreased brain weight – Decreased arborization of dendritic tree of neurones; reduced thickness of molecular layer of cerebellum • Retrognathia (underdevelopment of the maxilla and/or maxilla) Diffuse Hyperplastic Goiter • Pet Birds – Intrathoracic location of the thyroid glands – Functional disturbances – Treatment • One drop of Lugol’s solution/ounce of drinking water per day – Prevention • One drop of Lugol’s solution/ounce of drinking water once per week (Lugol’s solution: 5 gm iodine/100 ml; 10 gm KI/100ml) Berlin 2017 Thomas Rosol 15 Diffuse Hyperplastic Goiter • Fish (captive) – Location of thyroids under operculum near gills – Change in diet provides inadequate iodine intake – Thyroid enlargement due to TSH-mediated follicular cell hypertrophy and hyperplasia Colloid Goiter • ‘Macofollicular’ goiter • Occurrence and etiology – Reduced severity of iodine deficiency: partial or complete correction – Decreased demand for T4/T3 in young adults • Pathogenesis – Involutionary