Thyrotoxicosis- complete review of anatomy, physiology, types and clinical features, treatment and Recent advances

this presentation covers extensive pictures for clear explanation. this includes the anatomy & physiology of thyroid gland, a case review, types, clinical features and treatment of thyrotoxicosis. and the most intersting part it, it also includes Recent Advances in field of thyrotoxicosis

1. Anatomy & physiology of thyroid gland SURJEET ACHARYA

2. Thyroid gland - anatomy Size : Lobes :5cm x 2.5cm x 2.5cm Isthmus: 1.2cm x 1.2 cm Weight: 25g

3. Capsules of thyroid gland True fibrous capsule False fascial capsule Suspensory ligament of Berry

4. On deglutation Thyroid to hyoid – thyrohyoid Thyroid to cricoid – cricothyroid When mylohyoid contracts – hyoid pulled up

5. Parts & relations An Apex A Base 3 Surfaces : Lateral, Medial, Posterolateral 2 Borders : Anterior and Posterior

6. Arterial supply

7. Thyroid ima artery

8. Venous drainage

9. Tubercle of zuckerkandl

10. Nerve supply

11. Lymphatics

12. Histology Large no of closed follicles Filled wit colloids Lined by cuboidal cells Major constituents – thyroglobulins Blood flow 5times the weight

13. Physiology of thyroid gland Formation and Secretion of thyroid hormones – T3 & T4 Metabolic Functions Regulation of their hormones

14. Steps in synthesis Iodide trapping Oxidation of Iodide ion Organification of thyroglobulin Coupling of Iodotyrosine residues Release of T3 & T4 into blood

15. Daily rate of secretion of hormones Thyroxine – 93% Triiodothyronine – 7% 1/4 th of T4 deiodinated to additional T3 Hormones delivered & used by tissues as T3

16. Transport of T3 & T4 Bound to plasma proteins – TBG, TBPA & albumin Released slowly to tissue cells because of high affinity to plasma proteins ( T4 – 6 days, T3 – 1 day) Binds with intracellular proteins, stored in target cells, released slowly over periods Slow onset & long duration of action

17. Metabolism and excretion Intracellular thyroid hormone receptors high affinity to T3 Before acting on target cells, deiodinase (D1&D2) enzymes remove one iodide from most of T4 D3 responsible for inactivating T3 and preventing activation of T4 by converting it into RT3 After inactivation, T3 conjugated with sulfates & glucuronides, excreted in bile, partially reabsorbed after deglucuronidation in intestines

18. Effect on cellular metabolic activity Increases number & activity of mitochondria Increases active transport of ions through cell membranes Effect on other endocrine glands Controls rate of secretions of other glands Effect on sexual function Promotes normal functioning

19. Functions of TSH Increased proteolysis of Tg Increased activity of iodide pump Increased iodination of tyrosine Increased size & secretory activity of thyrois cells Increased number of thyroid cells

20. THYROTOXICOSIS & HYPERTHYROIDISM Thyrotoxicosis- Symptom complex due to raised levels of thyroid hormones Hyperthyroidism- Thyrotoxicosis due to overproduction of thyroid hormones by the thyroid gland Hyperthyroidism is one of the causes of thyrotoxicosis Thyrotoxicosis can occur due to causes other than hyperthyroidism

21. HYRERTHYROIDISM Primary thyrotoxicosis – Graves disease, exophthalmic goitre, diffuse goitre ( Basedow’s disease ) Secondary thyrotoxicosis – Secondary to multinodular goitre ( Plummer disease ) Tertiary thyrotoxicosis – Solitary toxic nodule – Autonomous nodule not under control of TSH but due to hypertrophy and hyperplasia of the gland ( Goetsch’s disease )

22. RARE CAUSES Thyrotoxicosis factitia – drug induced- L thyroxine Jod Basedow thyrotoxicosis – because of large doses of iodides given to a hyperplastic endemic goiter Autoimmune thyroiditis or de Quervain’s thyroiditis Neonatal thyrotoxicosis Struma ovarii Drugs like amiodarone - an antiarrhythmic agent. Amiodarone is rich in iodine having structural similarity to T4 causing thyrotoxicosis Well differentiated carcinoma can cause thyrotoxicosis- metastatic type Hydatidiform mole or choriocarcinoma with high levels of ß HCG can stimulate TSH receptor- thyrotoxicosis

23. GRAVES DISEASE Most common cause of hyperthyroidism Named after Irish physician Robert Graves Also referred as Basedow’s disease after Karl von Basedow who also described cases Autoimmune disease with TSH receptor antibodies in blood

24. ` TSI/ TsAb and LATS cause pathological changes in thyroid Histologically acinar cell hypertrophy and hyperplasia with absence of normal colloid in the tall columnar epithelium Familial Puberty, pregnancy, emotion and infection – precipitating factors

25. TOXIC ADENOMA Benign functioning monoclonal thyroid tumour Solitary nodule of thyroid Autonomous functioning tumour; not TSH responding Secretes large quantity of thyroid hormones suppressing the function of remaining normal thyroid tissue No eye signs and other features of Graves disease Higher T3 levels than T4 TSH receptor or G protein- somatic mutation USG, T3,T4, TSH, Radioisotope scan (hot nodule)

26. T3 TOXICOSIS T3 alone is raised TSH decreased T4 normal Free T3 estimation is important

27. SUBCLINICAL HYPERTHYROIDISM Decreased TSH level but not undetectable with T3, T4, free T3, free T4 are within the normal range without any clinical symptoms Its incidence is 1% of hyperthyroidism Cause of infertility in females May present as cardiomyopathy or arrhythmias Hormone assay, radioisotope scan and US neck, ECG

28. STRUMA OVARII Ovarian teratoma with thyroid differentiation will secrete T3, T4 and suppress TSH Function of normal thyroid in neck is suppressed Radioisotope scan shows uptake in pelvis with no or less uptake in neck

29. HASHITOXICOSIS Due to autoimmune Hashimoto’s thyroiditis Mild toxic features develop during initial stage of hyperplasia Already formed thyroid hormones are released by inflamed gland causing toxicity

30. THYROTOXICOSIS FACTITIA Intake of L thyroxine without indications to lose weight or Overdose intake of L thyroxine Causing toxicity

31. Postpartum hyperthyroidism Exacerbation of previously confirmed or undiagnosed hyperthyroidism during pregnancy due to increased autoimmune factors It is associated with HLA DR3 and HLA DR5

32. NEONATAL THYROTOXICOSIS In infants born to mother with Graves disease due to crossing of the thyroid stimulating antibody across placental barrier Infant will be toxic for 3-4 weeks which subsides gradually

33. TROPHOBLASTIC THYROTOXICOSIS HCG secreted from vesicular mole, choriocarcinoma or metastatic embryonal carcinoma in females, acts like TSAb causing toxicity

34. Jod basedow thyrotoxicosis Patient with hyperplastic endemic goitre takes large doses of iodine , taken up by hyperplastic gland in large quantity causing temporary hyperthyroidism It differs from Basedow disease (Graves disease)

35. Apathetic hyperthyroidism Lacks all usual clinical features of toxicity Old people Thyroid gland is not enlarged Behavioral problems Recent angina or atrial fibrillation Diagnosis is masked

36. Subacute thyroiditis A destructive release of preformed thyroid hormone Radioactive iodine uptake in the thyrotoxic phase of the disease Thyroid hormone levels can be highly elevated Low ESR, low T3 T4 ratio

37. Clinical Features of Thyrotoxicosis

38. History ? BEFORE SUBJECT PROPER….

39. An 11-year-old female with no significant past medical history presented with symptoms like weight loss and heat intolerance. She has also experienced a decline in grades at school. Family history is significant for thyroid disease in both grandmothers (both on thyroid replacement therapies). The clinician ordered thyroid function tests ; Free T4, T3, TSH, anti-TSH receptor antibodies, antithyroglobulin and antithyroid peroxidase antibodies.

40. The results for the tests follow: Free thyroxine (FT4)  2.87 ng / dL (Increased) Triiodothyronine pediatric (T3)  374.00 ng / dL (Increased) Thyroid-stimulating hormone (TSH) <0.018 uU /ml (Decreased) Thyroxine (T4)  18.2 ug / dL (Increased) Antithyroglobulin antibodies  >3000 IU/ml (positive) Antithyroid peroxidase antibodies  2667 IU/mL (Positive) Anti-TSH receptor antibodies  69.6 % (Increased)

41. Diagnosis Graves's disease (hyperthyroidism with thyrotoxicosis) * http://path.upmc.edu/cases/case537.html Contributed by Anca V. Florea , MD and Mohamed A. Virji , MD, PhD

42. Objectives To elaborate on Clinical features in a patients with THYROTOXICOSIS. Symptoms Signs Eye signs Cardiac Manifestations Myopathy Pretibial Myxoedema Thyroid acropathy Other features

43. Symptoms

44. Goitre Primary Thyrotoxicosis Diffuse Vascular Large or small Firm or soft Thrill/ Bruit Secondary Thyrotoxicosis Nodular Insidious

45. Gastrointestinal System

46. Cardiovascular System

47. Genitourinary system

48. Skeletal system

49. Neuromuscular System

50. Integument

51. Psychiatry

52. Sympathetic Overactivity

53. Signs

54. Eye Signs Lid Retraction

55. Von Graefe’s sign (Lid Lag)

56. Stellwag’s sign

57. Exopthalmos

58. Corneal ulceration

59. Malignant Exophthalmos

60. Grading Of Exophthalmos Mild  Widening of Palpebral fissure due to lid retraction Moderate  Orbital deposition of fat causing bulging with positive Joffroy’s sign Severe  Congestion with intraorbital oedema, raised intraocular pressure,diplopia and ophthalmoplegia Progressive  Inspite of proper treatment progression of eye signs is seen with chemosis , corneal ulceration and ophthalmoplegia .

61. Pulse Rate Tachycardia (Crile’s grading) Sleeping PR – Three consecutive nights-Average. Grading of PR Grade I  <90/min Grade II 90-110/min Grade III >110/min

62. Other CVS manifestaions Atrial Fibrillation Atrial flutter Extrasystole tachycardia Wide pulse pressure

63. Myopathy Weakness of proximal muscles (Thigh and arm muscles)  Basedow Myopathy Weakness more during isometric contraction(getting down steps, lifting a bucket) Severe( resembles Myaesthenia gravis)

64. Pretibial Myxoedema Primary Thyrotoxicosis Bilateral, symmetrical,shiny , red thickened dry skin with coarse hair in the feet and ankles. Severe  skin of leg also get involved. Due to deposition of Myxomatous tissue in skin and subcutaneous plane. Associated with exophthalmos with high levels of thyroid stimulating antibodies. Skin cyanotic on cold exposure. Thyroid dermopathy Pretibial myxoedema, pruritus, palmar erythema, Hair thinning, Dupytren’s contracture.

65. Thyroid acropachy Clubbing of fingers and toes Primary thyrotoxicosis Hypertrophic pulmonary Osteoarthropathy .

66. Others Thrill in the upper pole of thyroid and Bruit on auscultation. Hepatosplenomegaly

67. INVESTIGATIONS

68. TRH TSH T3 AND T4 ----

69. * TSH- Thyroid stimulating hormone ( 0-5IU/ml). * T3 f- (3-9nmol/l). * T4 f-(8-26nmol/l). * RA I 123 . *TRH stimulation test- obsolete nowadays. *Serum cholesterol. *BMR- basal metabolic rate. * Thyroid auto antibodies . *Werner’s T3 suppression test . *Thyroglobulin estimation study.( 0.5-50micg/l) * FNAC of thyroid.

70. PRIMARY HYPERTHYROIDISM- INTRINSIC Etiology- Grave’s disease(most common) Intake of iodine supplements Inflammation (viral, certain medications and pregnancy) Carcinoma of the thyroid Toxic adenoma.

71. TSH- HIGH RADIO ACTIVE IODINE UPTAKE. T4 TEST- USG SCAN Thyroid antibodies test- Thyroid peroxidase antibody . - Thyroglobulin antibody .

72. RA Iodine123 Cold nodule or hot nodule. Done in MNG Solitary thyroid nodule Retrosternal goiter Graves disease struma ovary Follicular carcinoma to rule out secondaries Contra indication- Pregnancy and lactation.

73. SECONDARY HYPERTHYROIDISM- EXTRINSIC Etiology- Thyroid stimulating hormone secreting pituitary adenoma Gestational thyrotoxicosis HCG producing tumor.

74. TSH- T3 AND T4- TRH- USG of the thyroid CT scan of the head or MRI of brain to detect tumors in the pituitary gland.

75. T3 TOXICOSIS It is observed in some cases of toxic nodular goiter and most importantly with a solitary hyperfunctioning nodule. This should be suspected T4 I normal and absence of thyroxine binding globulin. Do a t3 suppression test.

76. Serum cholesterol increased in hypothyroidism BMR increased in hyperthyroidism Thyroid antibodies- primary thyrotoxicosis Thyroglobulin estimation- used during follow up period especially in follicular carcinoma. Post thyroidectomy its level decreases. Follow up marker in well differentiated thyroid carcinoma. Sudden raise occurs in thyroiditis , primary or secondary toxic goiter.

77. FNAC To investigate the pathology. Used in the diagnosis of papillary ,medullary , anaplastic carcinomas, cold nodules , thyroiditis. 23G needle is used . Minimum 6 aspiration is done. Done in suspicious solitary/multiple nodule /dominant nodules. Mostly done under ultra sound guidance.

78. USG Identifies nodules, number , size ,vascularity ,echogenicity . For USG guided FNAC. To identify neck lymph nodes To identify solid or cystic lesions Benign lesion is hyperechoic , often cystic with well differentiated margins, shows egg shell calcifications as a rim . Malignant lesions is hypoechoic with poor margins with high vascularity, without any perfect halo.

79. TRH STIMULATION TEST It’s a test for hypothalamic –pituitary axis . IV TRH- 200micg- RISE in TSH in 20 minutes and reaches to normal in 20 minutes. In pituitary insufficiency – TH deficiency – SUB NORMAL response In hypothyroidism – elevated TSH. This test is useful in doubtful hyperthyroidism,hypothyroidism,t3 toxicosis and in ophthalmic graves disease.

80. Thyrotoxicosis Management

81. Anti-Thyroid Drugs

82. Indications: Toxicity in pregnant women Toxicity in children and young adults Before thyroidectomy Soon after starting radioactive I therapy 131

83. Action: Carbimazole - acts by blocking thyroid hormone synthesis and suppresses autoimmune process in thyroid in grave’s disease. Propylthiouracil - blocks thyroid hormone synthesis and blocks peripheral conversion of T4 to T3.

84. Dose: Carbimazole- 10mg x 3 or 4 times/ day, latent interval- 7 to 14 days and maintenance dose- 5mg x 2 or 3 times/day for 6-24 months Propylthiouracil- 200mg 8 th hourly Alternative: Initial high dose of Carbimazole followed by maintenance dose of 0.1-0.15mg thyroxine daily

85. Side effects: Fever Rash Neuritis Agranulocytosis Lymph node enlargement Arthralgia Myalgia Psychosis Liver cell dysfunction Hepatotoxicity

86. Propranolol : dose:40mg tid Action: reduces cardiac problems blocks peripheral conversion of T4 to T3

87. Contraindications: bronchial asthma heart block cardiac failure

88. Advantages: No surgery No use of radioactive substances Disadvantages: Prolonged treatment Failure rate-50%

89. Contraindicated Large gland size Severity of disease TSH- RAb levels

90. Indications: Failure of drug treatment Autonomous toxic nodule Nodular toxic goitre Malignancy can’t be ruled out Graves in children, or with nodules Need for antithyroid drugs >2 years Large goitre, substernal/ intrathoracic goitre Pressure symptoms, Graves ophthalmopathy Amiodarone-induced thyrotoxicosis

91. Lugol’s iodine: decreases vascularity of the gland & makes more firm and easier to handle during surgery Dose: 10-30drops/day for 10 days prevents the release of hormone from the gland- Thyroid Constipation After 2 weeks effect - lost causing thyroid escape from iodine control

92. Advantages: Rapid and high cure rate Radioiodine therapy avoided Tissue for biopsy, removes occult malignant foci Best option for ophthalmopathy Women planning for a child Coexisting parathyroid carcinoma- removed For intrathoracic retrosternal toxic thyroid

93. Disadvantages: Recurrent thyrotoxicosis Thyroid insufficiency Complications of surgery itself Hypothyroidism

94. RADIOACTIVE IODINE Destroys thyroid cells and reduces the mass of functioning thyroid tissue to below a critical level

95. 131 123

96. Therapeutic purposes: I 300-600MBq orally Maintenance dose of L-thyroxine 0.1mg daily Diagnostic purposes: I given on empty stomach orally on previous day of diagnosis Dose: 5 micro curie 131 123

97. Indications: Primary thyrotoxicosis Autonomous toxic nodule Follicular carcinoma of thyroid Ectopic thyroid Retrosternal thyroid

98. Contraindications: Pregnancy and lactation Children Females desiring to have pregnancy within a year

99. Advantages: No surgery No prolonged medical therapy Disadvantages: Hypothyroidism Ophthalmopathy and Dermopathy - worsened Effects will be seen only after 3 months Induce hyperparathyroidism

100. Special conditions: Pregnancy: Radioiodine - absolutely contraindicated Surgery – miscarriage Antithyroid – thyroid insufficiency

101. Children: Radioiodine contraindicated Surgery- increased risk of recurrence because thyroid cells highly active after thyroidectomy in young.

102. Thyrocardiac: -seen in patient with severe cardiac damage due wholly or partly to hyperthyroidism -middle aged or elderly -secondary thyrotoxicosis -hyperthyroidism not very severe Treatment: Beta blockers, radioiodine with antithyroid drugs

103. Proptosis of recent onset: Termination of thyrotoxicosis by thyroidectomy or radioiodine when proptosis is recent onset – result in malignant exophthalmos.

104. High titres of thyroid antibodies: Indicates lymphatic infiltration of goitre i.e. diffuse or focal thyroiditis. Treatment: anti-thyroid drugs If medical treatment fails surgery or radio-iodine is contraindicated. steroids - reduce pain and swelling

105. RECENT ADVANCES IN THYROTOXICOSIS

106. overview Advances in diagnosis Advances in surgery - MITS - MIVAT - ROBOTIC Summary

107. Diagnostic advances

108. Radioactive iodine and Tecnitium99 scan Radioactive iodine(I123) Tecnitium99 (Tc99) costly Cheap Oral intake on empty stomach IV injection Half life is 13 hours Half life is 6 hours

109. Radioactive iodine scan

110. Tc99

111. Normal Grave’s MNG Txadenoma Thyroiditis

112. SURGICAL ADVANCES

113. Long neck scar makes patients uncomfortable in public/ cosmetic

114. Scar length reduced but still, cosmetically not acceptable

115. Minimally Invasive Thyroid Surgery (MITS) First endoscopic thyroidectomy was done by HUSHER ET AL in 1997. Hüscher CS, Chiodini S, Napolitano C et al (1997) Endoscopic right thyroid lobectomy . Surg Endosc 11(8):877 KANG ET AL started using Axillary approach for thyroidectomy Kang J, Ikeda Y, Takami H, Sasaki Y et al (2000) Endoscopic neck surgery by the axillary approach. J Am Coll Surg 191(3):336–340

116. MICCOLI ET AL introduced MINIMALLY INVASIVE VIDEO ASSISTED THYROIDECTOMY (MIVAT) Miccoli P, Berti P, Frustaci GL et al (2006) Video-assisted thyroidectomy : indications and results. Langenbecks Arch Surg 391(2):68–71 LOMBARDIE ET AL evaluated patients undergone (retrospective study of 1350 patients) MIVAT and CT and reported MIVAT had superiority over CT Lombardi CP, Raffaelli M, Princi P et al (2005) Safety of video-assisted thyroidectomy versus conventional surgery. Head Neck 27(1):58–64

117. Axillary approach

118. Advantages: Reduced tissue trauma Short hospital stay Better cosmetic results Minimal postop pain Patient more comfortable

119. Disadvantages: Longer duration of surgery Costly Steep learning curve More than 1 surgeon required

120. Patient selection for MITS INDICATIONS CONTRAINDICATIONS Thyroid nodule size <35mm (benign) and <20mm (malignant) Malignancy other than low risk Papillary carcinoma thyroid Thyroid gland volume <30ml on USG Gland volume >30ml No previous neck surgeries Associated enlarged lymph nodes No H/o irradiation Extra thyroidal extension, substernal extension No H/o thyroiditis Obese patient

121. TECHNIQUE ADV DISADV MIVAT Small incision Reduced pain Short postop Less tissue trauma No drains required Only for small thyroid <30cc Long duration of surgery Steep learning curve MIT Small incision Better cosmetic scar Long duration of surgery

122. What more to come in future????

123. Thyroid surgery through transoral route Robotic thyroid surgery

124. Robotic thyroid surgery da Vinci system Computer motion system Zeus robotic system

125. Advantage Disadvantage Spectacular view of surgical view Stable and accurate movement Still evolving Facilitates multiplanar dissection Cost of instillation of the system and maintanence Proper exposure of primary site without constant retraction for better visualisation Lack of training of young surgeons Better tissue dissection as the tip if the endoscope is in close vicinity to the tissue

126. Summary Use of radioactive iodine/Tc99 for diagnosis alongwith conventional diagnostic techniques Use of new surgical technique like MIT/MIVAT over conventional thyroidectomy Use of robotic surgery Future holds more!!!!

127. Thank you SURJEET ACHARYA