2 Thyroid Hormones Thyroxine (T4, tetraiodothyronine) Liothyronine (T3, triiodothyronine)Iodinated diphenyl ether structureBuilt and stored on thyroglobulin>99% protein bound in plasmaOnly free form has physiologic effectsT3 more potent; T4 longer lastingPeripheral deiodinationNoncovalent protein binding.
3 Physiological Effects Increases transcription (nuclear)Increases mitochondrial metabolismNet effects are target dependentOxygen consumptionHeat productionMetabolism, growth, differentiationPromotes effects of hormonesSteroids, catecholaminesNo effects on brain, spleen, testes
4 Thyroid Anatomy Healthy thyroid not palpable. Extends from C5 – T1. “Thyroid” from the Greek, meaning “shield”.
5 Thyroid Structure Hypothyroid Euthyroid Hyperthyroid Unique endocrine organ, in having large extracellular storage space.HypothyroidEuthyroidHyperthyroid
7 Thyroid Biosynthesis Iodide Trapping Thyroglobulin Synthesis IodinationCouplingProteolysis to release T3/T4Deiodination and recycling
8 Thyroid BiosynthesisDietary iodine (I2) converted to iodide (I-) for absorption. Active transport to achieve 30X in lumen vs plasmaThyroglobulin synthesis in ER -> golgi -> exocytosis into lumenI- oxidized into I2 by TPO. MIT and DIT (TPO dep).Coupling occurs on apical microvilli.Endocytosis into vesicles -> proteolysis (cathepsins) to cleave T3/T4
14 Thionamide MOACoupling is also highly sensitive to drug
15 Thionamide Side Effects Rash/itchFeverRarely:Liver dysfunctionLeucocytopenia
16 Other Antithyroid Options Iodide loadingHigh doses can inhibit iodide formationEffect transientMay be useful prior to RAI or surgeryDebulk and devascularize glandSide effectsRash, hypersalivation, oral ulcersCI in pregnancy (may cause fetal goiter)
17 Other Antithyroid Options Beta BlockersAdjunctive treatmentMay reduce T4 -> T3 conversionControl HR and palpitations, sweatsRapid actionCorticosteriodsReduce T4 -> T3 conversionMay reduce TSHR antibody effect in Grave’sContraindicated in asthma or reactive airways disease.
18 Case ReportPatient started on PTU 200 mg BIDand propranolol 40 mg TID, becoming euthyroid in 6 weeks whereupon the propranolol was tapered and D/C’dRemained on maintenance PTU for one year (50 mg bid) then discontinued and remained well for 3 yrsSymptoms recurred and PTU + propranolol was re-instituted for symptomatic relief. After 7 weeks, she developed a whole body red itchy rashShe received Na131I in a dose of 10 mCi by mouth for definitive control of her hyperthyroidism
19 Thyroid Storm Potentially life threatening Combined treatment strategy High dose PTUGive 1st; iodide will reduce drug uptake in glandIodide loading (IV Lugol’s solution)Beta blockersCorticosteriods
25 Case Report3 months later, she returned with lethargy, fatigue, coldness at room temperature, puffiness around the eyes and constipationLabs showed free T4 = 8 pmol/L, free T3 = 2 pmol/L and TSH = 8 mU/mL confirming hypothyroidismLevothyroxine 0.1mg daily was instituted and after 6 weeks, blood tests showed a TSH level of 3.2 mU/mL and all symptoms had resolvedShe has remained well on this regimen for 2 years
27 Parathyroid Basics Parathyroid Hormone Small molecule (34 amino acids) Activity based on amino terminalNo disulfide linkagesEncoded on chromosome 11Half-life only 2 – 4 minutesSecreted by chief cells
29 Hypoparathyroidism Decreased bone resorption & osteocytic activity HypocalcemiaIncreased neuromuscular excitabilityTetanic muscle contractions/spasmsSeizureProlonged QT intervalCataractTrousseau SignChvostek SignLow or absent iPTH
30 Hypoparathyroidism Causes Surgical (most common) Idiopathic Functional Genetic familial formsCirculating receptor antibodiesFunctionalDue to hypomagnesemiaMg2+ necessary for PTH release
31 Psuedohypoparathyroidism Target organs resistant to PTHCongential defect of PTHR1Plasma Ca2+ lowPlasma phosphate highRenal phosphatase activity high
32 Hypoparathyroidism Maintenance Treatment Acute Treatment Combined oral calcium + Vitamin DPhosphate restriction may be usedAcute TreatmentTetany or Hungry Bone SyndromeParenteral calcium followed by vitamin D supp + oral calcium
33 Hyperparathyroidism Primary Excess PTH high calcium, low phosphate Tumor, adenoma, hyperplasiaMore common in womenMarrow fibrosisOsteitis fibrosa cysticaMetabolic acidosisIncreased Alk Phos (bone)Kidney stones
34 Hyperparathyroidism Primary – Diagnosis Multiple elevated Ca2+ serum testsElevated iPTHAlk Phos typically lowCorticosteroid suppression testPrednisolone reduces serum Ca2+Indicates non-parathyroid originSarcoid, vitamin D intoxication, etc.
35 Hyperparathyroidism Treatment Acute Severe forms Other Agents Adequate hydration, forced diuresisOther AgentsCorticosteroids – Blood malignanciesMythramycinToxic antibiotic used to inhibit bone resorption – hematologic and solid neoplasms
36 Hyperparathyroidism Treatment Other Agents Calcitonin Biphosphonates Inhibits osteoclast activity and bone resorptionBiphosphonatesGiven IV or orally to reduce bone resorptionEstrogenCan be given to postmenopausal women with 1° hyperparathyroidism as medical therapy
38 2° Hyperparathyroidism Adaptive & unrelated to intrinsic disease of glandsDue to chronic stimulation of glands by low serum Ca2+ levels
39 2° Hyperparathyroidism CausesDietary deficiency of vitamin D or Ca2+Decreased intestinal absorption of vitamin D or Ca2+Drugs such as phenytoin, phenobarbitalRenal FailureDecreased activation of vitamin D3Hypomagnesemia