This document provides an overview of thyroid gland anatomy, physiology, and disorders. It describes the thyroid's role in the hypothalamic-pituitary-thyroid axis and hormone synthesis. Disorders discussed include hyperthyroidism, hypothyroidism, myxedema, cretinism, and thyroid cancer. For each, the document outlines pathophysiology, clinical presentation, diagnostic evaluation, and management.

1. Disorders of the Thyroid GlandClinical Medicine IElizabeth Bunting, MS, PA-CMarch 21, 2011

2. ObjectivesDescribe the anatomy of the thyroid gland, with regard to its relationship to:Other structures in the neckThe parathyroid glandsThe major vesselsEmbryologic developmentDescribe the regulation of thyroid metabolism, particularly:The role of the thyroid gland in the hypothalamus-anterior pituitary-thyroid axisThe role of iodine within the gland in controlling thyroid function

3. ObjectivesDiscuss the synthesis and secretion of thyroid hormone, describing:The two principal thyroid hormones secretedTheir relative utilization within the bodyHow they are chemically relatedDescribe the action of the hormones, particularly:The location of the receptors for thyroxine and triiodothyronine and their functionThe hormonal effect on cellular metabolism and developmentDefine hyperthyroidism, list and describe the:Associated pathophysiologyCommon clinical presentationsSignificant historical and physical exam findingsDiagnostic testsManagement

4. ObjectivesDefine thyrotoxicosis, and describe its pathophysiology, clinical presentation, diagnostic work-up and management.Define hypothyroidism, list and describe the:Associated pathophysiologyCommon presentationsSignificant historical and physical exam findingsDiagnostic testsManagementDefine myxedema and myxedema coma, and describe their pathologic process, clinical presentation, diagnostic work-up and management.Identify the different forms of thyroiditis and their distinguishing features and management

5. ObjectivesDescribe the various therapies, such as:Use of surgery, radioactive iodine, or anti-thyroid drugs for hyperfunctionUse of thyroid hormone for hypofunctionList and describe the types of thyroid cancer.Explain the signs and symptoms, pathophysiology and epidemiology of thyroid cancer.Discuss the diagnostic work-up and management of thyroid cancer.Discuss the prognosis for each of the major types of thyroid cancer.

6. Thyroid Anatomy

7. Parathyroid Glands

8. Embryonic Development of the Thyroid Gland and hormones

9. Thyroid Physiology

10. Thyroid PhysiologyMakes Thyrotropin Releasing Horomone(TRH)HypothalmusAnteriorPituitaryMakes Thyroid Stimulating Hormone (TSH) MakesT3(Triiodothyronine)& T4 (Thyroxine)Thyroid Gland

11. Thyroid Produces two related hormonesT3 – triiodothyronineT4 – thyroxineThese hormones play a critical role inThermogenic homeostasis in adultsMetabolic homeostasis in adultsCell differentiation during development

12. Regulation of the Thyroid AxisTSH is the most useful physiologic marker of thyroid hormone actionT3 and T4 are the dominant regulators of TSH productionTSH is released in a pulsatile manner and exhibits a diurnal rhythmHighest levels at night

13. Thyroid hormones T4 and T3 feed back to inhibit hypothalamic production of thyrotropin-releasing hormone (TRH) and pituitary production of thyroid-stimulating hormone (TSH).

14. TSH stimulates thyroid gland production of T4 and T3Thyroid hormone synthesis, metabolism, and actionIodide uptake is a critical first step in synthesis

15. Deficiency is prevalent in many mountainous regions globally and if present, may lead to goiter

16. If severe deficiency – hypothyroidism and cretinism

17. Recommended daily intake

18. 150 μg/d adults

19. 90-120 μg/d childrenGoiter

20. Thyroid hormone synthesis, metabolism, and actionIodide enters the thyroid and is used in production of both T3 and T4

21. T4 contains 4 iodine atoms

22. Removal of one of the iodine atoms leads to production of the potent hormone triiodothyronine (T3)T4 may be thought of as a precursor for the more potent T3T4 is converted to T3 in the peripheral tissues

23. Thyroid hormone synthesis, metabolism, and actionHormones are released from the thyroid and the vast majority are protein bound and deposited in peripheral cells

24. Once in cells, hormones act as nuclear receptors

25. T3 99.7%

26. T4 99.98%

27. The unbound hormone is available to tissues

28. Serum concentrations

29. T3 0.14 μg/dL

30. T4 8 μg/dLThyroid hormone synthesis, metabolism, and actionLaboratory evaluation of thyroid hormonesTSH – first thing you assessNormal range 0.5-5 μU/mlNormal result excludes a primary abnormality of functionSuppression = hyperthyroidElevated=hypothyroidIf abnormal TSH getFree T4 Normal 0.8-2.8 ng/dLElevated=hyperthyroidSuppression=hypothyroid

31. Thyroid hormone synthesis, metabolism, and actionTests to determine the etiology of thyroid dysfunction

32. Anti-TPO – antithyroidperoxidase antibody

33. Used to detect autoimmune thyroid disease

34. Up to 80% of those with Graves’ disease have TPO antibodies

35. 90% of those with Hashimoto’s thyroiditis have TPO antibodies

36. Thyroid scanning and ultrasound

37. Nuclear imaging

38. Radioisotopes of iodine are selectively transported into the thyroid allowing for imaging

39. Ultrasound

40. Used in nodular thyroid disease

41. Can detect nodules >3mm

42. Also useful in eval of recurrent thyroid cancerHypothyroid Disorders

43. HypothyroidismInsufficiency in the amount of thyroid hormone in the bodyPRIMARY HYPOTHYROIDISM: thyroid gland failure despite proper stimulation from the pituitarySECONDARY HYPOTHYROIDISM: failure of the pituitary to produce TSH to stimulate the thyroid glandTERTIARY HYPOTHYROIDISM: failure of the hypothalamus

44. Primary HypothyroidismGeneral ConsiderationsCommon: affects 1% of the general population and 5% over the age of 60Women > men 4:1 ratioMean age at diagnosis is 60 yearsPrevalence increases with ageThyroid hormone deficiency affects almost all body functions

45. Primary HypothyroidismCauses

46. Iodine deficiency

47. most common cause worldwide

48. Autoimmune disease

49. Hashimoto’s thyroiditis

50. Iatrogenic

51. treatment of hyperthyroidismTrauma to thyroid/pituitary/hypothalamusRadiation exposureSevere infectionNeoplasia (pituitary tumor)Drugs – glucocorticoids, phenobarbital, phenytoin, salicylates (large doses), fluorouracil, androgens, amiodarone, interferon

52. Primary HypothyroidismSymptomsCommon manifestationsWeight gainFatigue, lethargyDepressionWeaknessDyspnea on ExertionArthralgias/myalgiasMuscle crampsParesthesiasCold intoleranceConstipationDry skin, brittle hair and nailsHeadacheCarpal Tunnel SyndromeMenorrhagia

53. Primary HypothyroidismSymptomsLess commonDecreased appetite and weight losshoarsenessDecreased sense of taste and smellDeminished auditory acuitySigns BradycardiaDiastolic hypertensionThin, brittle nails, hairPeripheral edemaPuffy face and eyelids (myxedema)Skin pallor or yellowing (carotenemia)Delayed DTRGoiter

54. Primary HypothyroidismDiagnostic findings TSH Free T4TreatmentTreat the underlying cause if possibleThyroid replacement with T4Levothyroxine (Synthroid) Adults <60 years without evidence of heart diseaseStart with 25-75 μg qdRepeat TSH in 6 weeksAdjust dosage by 25 μg every 1-3 weeks based on TSHGoal – symptom relief and TSH in lower half of reference range

55. Primary HypothyroidismTreatmentAdults >60 years or patients with known cardiac diseaseStart with 25-50 μg qdMedication increases cardiac contractility and oxygen demand and don’t want to precipitate an MIRepeat TSH in 6 weeksAdjust dosage by 25 μg every 1-3 weeks based on TSHGoal – symptom relief and TSH in lower half of reference range

56. Primary HypothyroidismTreatmentAverage daily replacement dose is usually 1.7μg/kg body weight (typically 100-150 μg)Once full replacement is achieved and TSH levels are stable you can extend f/u visits to 6 months and then yearlyTake Levothyroxine (Synthroid) at least 4 hours between antacids, vitamins, seizure meds, food, lovastatin, sertraline – these medications affect T4 absorption or clearance

57. MyxedemaSevere hypothyroidism

58. Signs and symptoms

59. Severe Fatigue

60. Weakness

61. Cardiac enlargement (myxedema heart)

62. Pericardial effusions

63. Psychosis (myxedema madness)

64. Hypothermia

65. Stupor or myxedema coma

66. Hypoventilation, leading to hypoxia and hypercapnia

67. Pituitary enlargement due to hyperplasia of TSH secreting cellsMyxedemaDiagnostic studiesT4 lowTSH is increasedHyponatremiaHypoglycemiaAnemiaHypotension

68. MyxedemaTreatmentHigh mortality rate even with treatmentThyroid hormone replacement (initially IV then switch to oral)Levothyroxine 500μg IV bolusContinue orally at 50-100 μg/day

69. Myxedema ComaMedical emergencyOften induced by underlying infection: cardiac, respiratory, or CNS system illness, cold exposure or drug useMultiple organ abnormalities and progressive mental deteriorationVery rare, but has high mortality rateMost commonly results from stressful situations (e.g. trauma, surgery, burns, infection)Can occur because of coexisting disease states (e.g. diabetes, MI, fluid and electrolyte abnormalities)Can be precipitated by certain medications

70. Myxedema ComaTreatmentIV thyroid hormone replacementTreat underlying infection, if presentMonitor TSHMonitor glucose and sodium levelsWarming if hypothermia (blankets only)PrognosisMortality rate of 30 – 60%Poor prognosis if advanced age, bradycardia and persistent hypothermia

71. CretinismCongenital hypothyroidismEtiology1 in 4000 live birthsPathologyHypoplasia or aplasia of the thyroid glandOR failure of the gland to migrate into normal anatomic locationOR ineffective hormone due to enzyme deficiency

72. CretinismClinical featuresSluggishnessPale, gray, cool or mottled skinNonpitting myxedemaConstipationLarge tonguePoor muscle toneMental retardationDry, brittle hair

73. CretinismDiagnostic studiesLow T4Elevated TSHDelayed skeletal maturation on x-raysTreatment – thyroid hormone replacementPreventionNeonatal screening within 60 days of birthImproved prognosis with therapy started in first 2 months of life

74. Hyperthyroid Disorders

75. HyperthyroidismEtiologyGrave’s disease – most commonToxic multinodular goiter and thyroid adenomasSubacute (de Quervain) ThyroiditisExogenous thyroid hormoneStruma Ovarii (ovarian teratoma)No goiterPituitary tumor secreting TSHSecondary hyperthyroidismNormal or increased TSH with diffuse goiter and elevated T4Medication induced Amioderone

76. Grave’s diseaseEpidemiology Accounts for 60-80% of thyrotoxicosisFemales > males at 8:1Typically occurs between ages 20-40PathologyGrave’s disease is an autoimmune disorderInvolves the formation of autoantibodies that bind to the TSH receptors in the thyroid and stimulate gland hyperfunctionCharacterized by an increase synthesis and release of thyroid hormonesGland is typically enlargedFamilial tendency (HLA-B8 and HLA-DR3)

77. Grave’s diseaseSymptomsDescending order of frequencyHyperactivity, irritability, dysphoriaHeat intolerance, increased sweatingPalpitationsFatigue, weaknessWeight loss (increased appetite)DiarrheaPolyuriaOligomenorrhea, loss of libido

78. Grave’s diseaseSignsDescending order of frequencyTachycardia; A fib in the elderly, PACsTremorGoiter may be present (absence of goiter does not rule out hyperthyroidism)Skin warm, moistMuscle weakness, proximal myopathyExophthalmos, proptosis, lid lag with downward gaze (von Graefe sign) or retraction (Dalrymaple sign), staring appearance (Kicher sign)Thyroid dermopathy – pretibialmyxedemaHyperreflexiaThyroid acropachy (digital clubbing) rareHypokalemic periodic paralysis

79. Grave’s diseaseDiagnostic studies TSH T3 and T4 both total and freeAnti-TPO positive in up to 80%TSH receptor antibody (TRaB) positive in 65%ImagingThyroid RAI uptake and scanHigh in Grave’s Disease and toxic nodular goiterMRI of orbits if eye concerns

80. Grave’s diseaseManagementClinical features generally worsen without treatmentTreat by reducing thyroid hormone synthesis, using antithyroid drugs –propylthiouracil (PTU), methimazoleReducing the amount of thyroid tissue with radioiodine treatment (RAI)Causes progressive destruction of thyroid cellsReducing the amount of thyroid tissue with thyroidectomyIf not responding to medical treatmentLarge goitersBeta-blockers (propanolol) for symptoms during early treatment with antithyroid drugs and radioiodine tx

81. Thyroid StormRare Life-threatening emergencyExacerbation of hyperthyroidism/ thyrotoxicosisUsually precipitated by stress (surgery, infection, delivery, trauma)High mortality rate 30% even with treatment – cardiac failure, arrhythmia, or hyperthermiaPathology – same as hyperthyroidism with addition of stressor as above

82. DefinitionsHypothyroidism: hypoactive thyroid glandHyperthyroidism: hyperactive thyroid glandThyrotoxicosis: excessive thyroid hormoneThyroid storm: the life threatening result of excessive thyroid hormone and physical stressMyxedema: Severe result of lack of thyroid hormone

83. Thyroid StormClinical featuresExaggerated signs and symptoms of hyperthyroidismHigh feverMarked deliriumSevere tachycardiaSeizuresNausea, vomiting and diarrheaDehydrationComaJaundice Death

84. Thyroid StormDiagnostic studiesHighly elevated T3 and T4EKG may show sinus tachycardia, a-fib or flutterManagementAggressive use of and large dose of propylthiouracil (PTU)Oral or IV Ipodate Sodium(decreases thyroid hormone production) with Iodide given 1 hour later as Lugol solutionPropranolol given (cautiously if heart failure)Glucocorticoids (inhibits peripheral conversion of T4 to T3

85. Toxic Multinodular GoiterMultiple thyroid nodules that range in morphology from hypercellular regions to cystic areas filled with colloidWomen > menClinical presentationSubclinical hyperthyroidism or mild thyrotoxicosisUsually elderlyA fib, tachycardiaNervousness, tremorWeight lossRecent exposure to iodine, from contrast dyes or other sources, may precipitate or exacerbate thyrotoxicosis

86. Toxic Multinodular GoiterDiagnostic testingT3 and T4 with T3 elevated to a higher degree TSHThyroid scan shows heterogeneous uptake with multiple regions of increased and decreased uptakeTreatmentManagement is challengingAntithyroid drugs in combination with beta blockersHowever this treatment often stimulates the growth of the goiterRadioiodine can be used to treat areas of autonomySurgery provides definitive treatment

87. ThyroiditisClassificationsAcute thyroiditis (Suppurativethyroiditis)SubacutethyroiditisPainless or silent thyroiditisHashimoto’s thyroiditis (Chronic lymphocytic thyroiditis)Riedel thyroiditis

88. ThyroiditisAcute thyroiditisRareDue to suppurative infection of the thyroidTypically occurs in children or young adultsSigns and symptomsThyroid pain often referred to throat or earsSmall, tender goiter that may be asymmetricFever, dysphagia and erythema over the thyroidLaboratory ESR WBCNormal thyroid function

89. ThyroiditisDiagnostic testingFNA biopsy shows infiltration by PMN leukocytesCulture of the sample can identify the organismTreatmentAntibiotics guided by cultureSurgery may be needed to drain abscess

90. De Quervain’sThyroiditisAKA SubacuteThyroiditis, granulomatousthyroiditis, giant cell thyroiditisEtiology – probably viral, may be preceded by viral URISymptoms can mimic pharyngitisPeak incidence occurs between 30-50Women>men 3:1 ratio

91. De Quervain’sThyroiditisPathologyEnlargement and patchy inflammatory infiltrate of thyroidDuring initial phase of follicular destruction, there is release of thyroid hormones, leading to increased circulating T3 and T4 and suppression of TSHAfter several weeks, the thyroid is depleted of stored thyroid hormone and a phase of hypothyroidism typically occurs, with low free T3 and T4 and moderately increased TSH levelsFinally thyroid hormone and TSH levels return to normal as disease subsidesThyrotoxicosis hypothyroidism NL thyroid function lasts several weeks lasts 4-6 months returns within 12 months (develops in 50%)

92. De Quervain’sThyroiditisClinical featuresOften complain of sore throatExquisitely tender thyroid with small goiter (one or both lobes may be affected)Pain is often referred to jaw or earSometimes feverMalaise and URI symptoms may precede the thyroid-related featuresThere may be signs of thyrotoxicosis or hypothyroidism, depending on the phase of the illness

93. De Quervain’sThyroiditisDiagnostic studiesLymphocytosis on CBC Elevated ESRThyroid function tests evolve through 3 distinct phases over about 6 monthsThyrotoxic phase - T3 and T4 elevated, TSH suppressedHypothyroid phaseRecovery phaseNegative antibody testsLow thyroid radioiodine uptake (RAIU)

94. De Quervain’sThyroiditisTreatmentASA or NSAIDS typically sufficient to control symptomsMay use beta blockers for symptoms during thyrotoxicosis phaseThyroid hormone during hypothyroid stage may be neededRAI can be used to cause prompt fall of T3 and improve thyrotoxic symptomsMonitor thyroid function every 2-4 weeks using TSH and free T4

95. Painless ThyroiditisAutoimmune thyroiditisCategoriesSporadicOccurs in patients with underlying autoimmune thyroid diseasePostpartumOccurs in 7.2% of women 3-6 months after pregnancy3 times more common in women with type 1 diabetes70% chance of recurrence with subsequent pregnancies

96. Painless ThyroiditisClinical featuresClinical course similar to subacute thyroiditis except there is little to no thyroid tendernessThyrotoxicosis stage lasting 2-4 weeks followed by hypothyroid stage for 4-12 weeks, and then resolutionLabsPositive anti-TPONormal ESRManagementInitial stage usually mildCan use propranolol for symptoms if neededSecond stage – thyroxine replacement – use only for 6-9 months as recovery is the rule

97. Hashimoto’s ThyroiditisChronic lymphocytic thyroiditis due to autoimmunityEpidemiologyWomen > men 6:1 ratio14.3% of Caucasians10.9% of Hispanics5.3% of BlacksMean age at diagnosis is 60 yearsPrevalence increases with ageTends to be familial

98. Hashimoto’s ThyroiditisMost common type of thyroid disorder in the USPathologyImmune mediated destruction of thyroid parenchymaB-lymphocytes invade the thyroid gland which leads to follicular atrophy and then fibrosisInitially may have hyperthyroidism due to passive release of stored thyroid hormoneDetectable levels of anithyroid antibodies – anti-TPO or antithyroglobulin antibodies or bothOnly a small subset of individuals with elevated antithyroid antibody levels ever develop thyroid dysfunctionFound in 3% of men and 13% of women

99. Hashimoto’s ThyroiditisMay be associated with other autoimmune diseasesType I diabetes, Addison’s disease, pernicious anemiaSigns and symptomsMay be hyperthyroid, euthyroid or hypothyroidThyroid gland may be diffusely enlarged (goiter), firm or rubbery, usually nontenderSurface of thyroid may be irregular or nodularSlow progression to hypothyroidism over yearsPatients often present with signs and symptoms of hypothyroidismDry skin, decreased sweating, thinning of skin, myxedema, puffy face and eyelids, nonpittingpretibial edema, dry/brittle hair, depressionThyroid is diffusely enlarged, firm, and finely nodular

100. Hashimoto’s ThyroiditisDiagnostic studiesThyroid function testsHyperthyroid phase Free T4 levels higher than T3 due to it being the greater stored hormoneBecause T4 is less active than T3 the hyperthyroid symptoms are less severe than in other thyroiditis conditionsTSHHypothyroid stateFree T4 TSHPositive antithyroid antibodiesAnti-TPO in 90%Antithyroglobulin antibodies in 40%

101. Hashimoto’s ThyroiditisImagingUltrasound shows diffuse heterogeneous density and hyperechogenicityFNA for nodulesDoppler may be needed to distinguish between Graves Disease and Hashimoto’sTreatment Thyroxine hormone replacement If hypothyroidOr if euthyroid with goiter presentWill shrink the goiter by 30% in most cases over 6 months

102. Riedel ThyroiditisAKA Invasive fibrous thyroiditis, Riedel struma, woody thyroiditis, ligneous thyroiditis, invasive thyroiditisGenerally a manifestation of multifocal systemic fibrosis syndromeCauses hypothyroidism and sometimes hypoparathyroidismRAREGenerally found in middle-aged or elderly womenSigns and symptoms:Thyroid enlargement is asymmetrical and stony, hard and adherent to neck structures

103. Riedel ThyroiditisSigns and symptoms cont’d:Compression of the thyroid causes dysphagia, dyspnea, pain and hoarsenessFibrosis happens in other areas of the body as wellTreatmentTamoxifen can provide remission in 3-6 monthsShort term corticosteroids can help with compressionSurgical decompression may be needed

104. Thyroid NodulesMust consider cancerPathologyAdenomas, cysts, colloid nodules (most common nodules), localized thyroiditis, and cancer (mostly papillary and follicular)Clinical featuresMost are asymptomaticMay have hyper- or hypothyroidism

105. Thyroid NodulesClinical featuresSuspect cancer if rapid growth, fixed in place with no movement on swallowing, hx of neck radiation, male sex, extremes of ageDiagnostic studiesTSH and free T4Fine needle aspiration and cytologyUltrasound

106. Thyroid NodulesManagementMUST exclude malignancyTreatment according to specific diagnosisIf malignant, surgery followed by thyroid radioiodine ablation

107. Thyroid CancersEpidemiologyMost common malignancy of the endocrine systemUncommon, diagnosed in less than 1% of the populationWomen > men 3:1 ratio Male sex associated with worse prognosisIncidence increases with ageClassificationPapillary carcinoma (most common)FollicularMedullaryAnaplastic (most aggressive)

108. Thyroid CancersRisk Factors of thyroid cancer in pt with a thyroid noduleHistory of head and neck irradiationAge <20 or >45Bilateral diseaseLarge nodule size, >4cmNew or enlarging neck massMale sexNodule fixed to adjacent surfacesGenetic factors, especially medullary which has familial predisposition

109. Thyroid CancersSigns and symptomsPalpable, firm, nontender nodule in the thyroidMost are asymptomaticPossible hoarsenessPossible neck painPossible cervical LADOnly 5% of palpable thyroid nodules are malignantThyroid function tests are usually normal

110. Thyroid CancersDiagnostic studiesSerum calcitonin and CEA levels may be elevated in medullary cancerUsually seen as a “cold” nodule on radioactive iodine thyroid scanUltrasound shows solid, well-formed nodule/s and can detect metastases in the neckFNA neededCT scan – used to detect metastasesMRI and PET scans- distant mets

111. Thyroid CancersTreatmentSurgical excision with near-total thyroidectomy with post-surgical radioablation of the remnant thyroid tissueMost tumors are still TSH responsive, TSH suppression is a mainstay of treatmentGoal is TSH range 01.-0.5 IU/LChemo used if mets are present

112. Thyroid CancersPapillaryFollicularMedullaryAnaplasticIncidence MOST 2nd MOST Uncommon LEAST COMMON COMMON COMMONAv. Age 42 50 50 57Females 70% 72% 56% 2%Deaths 6% 24% 33% 98%I uptake + ++++ 0 0Degree of + ++-+++ +-++++ ++++++++Malignancy

113. Any Questions???

114. ReferencesJennifer Forbes, MHS, PA-C: many slides are hers from last yearCMDTHarrison’s Principles of Internal MedicineImages:www.riversideonline.com/.../DS00396.cfmehp.niehs.nih.gov/.../howdeshell-full.htmlhealthfiles.net/disease/toxic-nodular-goiter/www.missionfoto.com/images/fall03/goiter.html