Management of Thyroid Diseases & Emergencies

5th-year medical student seminar presentation under the supervision of Dr. Sudzilla, a specialist.

1. THYROID DISEASES & EMERGENCIES PRESENTED BY NURUL HIDAYU BINTI IBRAHIM NURUL HUSNA BINTI AZIZ MUHAMMAD AFFAN SYAFIQI

2. INTRODUCTION THYROID DISEASES Thyroid diseases are amongst one of the most common endocrine diseases in Malaysia. Through the hormones it produces, the thyroid gland influences almost all the metabolic process in the body. Thyroid diseases can range from a small, harmless goiter that needs no treatment to life threatening cancer. The most common thyroid problems involve abnormal production of hormones which are hyperthyroidism and hypothyroidism . Although the effects can be unpleasant or uncomfortable, most thyroid problems can be managed well if properly diagnosed and treated.

3. ANATOMY THYROID GLAND The thyroid is a butterfly-shaped gland located in the front of the neck just above the trachea, weighs approximately 15 to 20 grams in the adult human. It consist of two lobes connected by narrow band thyroid tissues called the isthmus. Four parathyroid glands located posteriorly at each pole of thyroid gland. Thyroid gland supplied by: Superior Thyroid Artery – branch of external carotid artery Inferior Thyroid Artery – branch of thyrocervical trunk Thyroid Ima Artery

4. ANATOMY THYROID GLAND

5. ANATOMY THYROID GLAND The venous blood is drained via: Superior thyroid veins Middle thyroid veins Inferior thyroid veins – drain into the left and right brachiocephalic veins drain to the internal jugular vein Lymphatic drainage: P relaryngeal lymph nodes Pretracheal lymph nodes Paratracheal lymph nodes Nerve supply: The gland receives sympathetic nerve supply from the superior, middle and inferior cervical ganglion of the sympathetic trunk . The gland receives parasympathetic nerve supply from the superior laryngeal nerve and the recurrent laryngeal nerve .

6. ANATOMY BLOOD SUPPLY OF THYROID GLAND

7. ANATOMY HORMONES OF THYROID GLAND Hormones secreted by thyroid gland: thyroxine (T4 ) triiodothyronine (T3 ) The T3 and T4 are created from iodine and tyrosine Hormones secreted by parathyroid gland: calcitonin All organ systems are affected by thyroid hormones. Thyroid hormones increase metabolic rate , heart rate , and ventricle contractility , as well as muscle and central nervous system (CNS) excitability .

8. ANATOMY HORMONES OF THYROID GLAND

9. PHYSIOLOGY THYROID GLAND The iodide trapped by the thyroid gland is subsequently oxidized to iodine by the enzyme thyroid peroxidase. The iodine then undergoes a series of organic reactions within the thyroid gland to produce tetraiodothyronine or thyroxine (T 4 ) and triiodothyronine (T 3 ). T 3  is also produced in other tissues such as the pituitary, liver, and kidney by the removal of an iodine molecule from T 4 . T 4  is considered to be more of a pro-hormone , while T 3  is the most potent thyroid hormone produced. T 4  and T 3 are both stored in the thyroglobulin protein of the thyroid gland and released into the circulation through the action of pituitary derived thyrotropin (thyroid stimulating hormone or TSH)

10. PHYSIOLOGY THYROID GLAND

11. PHYSIOLOGY THYROID GLAND Series of organic reaction: Iodine trapping Synthesis and secretion of thyroglobulin Oxidation of iodine Organification of thyroglobulin Coupling reaction Storage Secretion

12. RISK FACTORS FACTORS THAT AFFECT THYROID FUNCTION

13. TYPES THYROID DISEASES HYPOTHYROIDISM HYPERTHYROIDISM It occurs when the gland produces excessive amounts of thyroid hormones. T he most common cause is Graves' disease , an autoimmune disorder. Hypothyroidism is a state of insufficient thyroid hormone production . Worldwide, the most common cause is iodine deficiency. H ypothyroidism secondary to iodine deficiency remains the leading cause of preventable intellectual disability. In iodine-sufficient regions, the most common cause of hypothyroidism is Hashimoto's thyroiditis , also an autoimmune disorder.

14. TYPES THYROID DISEASES THYROIDITIS THYROID EMERGENCIES Thyroid Storm Myxedema Coma Autoimmune – Hashimoto’s thyroiditis, P ost-partum thyroiditis & Atrophic thyroiditis Infection – Viral thyroiditis (De Quervain’s thyroiditis) Physical – Radiation to the neck Idiopathic – Painless thyroiditis, Riedel’s thyroiditis

15. HYPOTHYROIDISM

16. INTRODUCTION RISK FACTORS Autoimmune thyroiditis Previous Graves' disease Personal or family history of associated autoimmune disorders ( eg , vitiligo, pernicious anaemia , diabetes mellitus type 1 ) Thyroidectomy or other neck surgery Radioactive iodine therapy External radiotherapy Drugs impairing thyroid function Lithium carbonate Amiodarone Hypothalamic disorders Pituitary disorders

17. INTRODUCTION CLASSIFICATION OF HYPOTHYROIDISM HYPOTHYROIDISM PRIMARY (90%) SECONDARY (Central) SUBCLINICAL TRANSIENT High TSH concentration Low serum free thyroxine (T4) concentration Low serum T4 concentration Serum TSH concentration is not appropriately elevated. Can be observed as a phase of subacute thyroiditis N ormal free T4 concentration E levated TSH concentration Other terms for this condition are : M ild hypothyroidism E arly thyroid failure P reclinical hypothyroidism

18. HYPOTHYROIDISM

19. PRIMARY HYPOTYROIDISM AUTOIMMUNE HYPOTHYROIDISM Autoimmune hypothyroidism may be associated with a goiter (Hashimoto's, or goitrous thyroiditis) or, at the later stages of the disease, minimal residual thyroid tissue (atrophic thyroiditis ). Because the autoimmune process gradually reduces thyroid function, there is a phase of compensation when normal thyroid hormone levels are maintained by a rise in TSH. Though some patients may have minor symptoms, this state is called subclinical hypothyroidism . Later, unbound T4 levels fall and TSH levels rise further; symptoms become more readily apparent at this stage (usually TSH >10 mIU /L), which is referred to as clinical hypothyroidism or overt hypothyroidism . Celebrities who known to has Hashimoto’s thyroiditis are Gigi Hadid & Kim Cattrall.

20. PRIMARY HYPOTYROIDISM PATHOGENESIS In Hashimoto's thyroiditis, there is a marked lymphocytic infiltration of the thyroid with germinal center formation, atrophy of the thyroid follicles accompanied by absence of colloid, and mild to moderate fibrosis . In atrophic thyroiditis, the fibrosis is much more extensive, lymphocyte infiltration is less pronounced, and thyroid follicles are almost completely absent. Atrophic thyroiditis likely represents the end stage of Hashimoto's thyroiditis rather than a distinct disorder . Genetic Associations: HLA-DR (3,4,5) & CTLA-4 (Cytotoxic T Lymphocyte associated antigen 4) polymorphism Modifying Environmental Factor : Chronic exposure to high iodine diet

21. PRIMARY HYPOTYROIDISM ASSOCIATED CONDITIONS Other Autoimmune disorders: Type 1 diabetes mellitus Addison's disease Pernicious anemia Vitiligo Alopecia areata Celiac disease RA, SLE, Sjogren syndrome Thyroid associated ophthalmopathy ( in 5% of pt ) Turner syndrome, Down’s syndrome Type 1 or 2 polyglandular autoimmune syndrome

22. SECONDARY HYPOTHYROIDISM INTRODUCTION Secondary hypothyroidism is usually diagnosed in the context of other anterior pituitary hormone deficiencies; isolated TSH deficiency is very rare . TSH levels may be low, normal, or even slightly increased in secondary hypothyroidism; the latter is due to secretion of bio inactive forms of TSH . The diagnosis is confirmed by detecting a low unbound T4

23. HYPOTHYROIDISM CLINICAL MANIFESTATION Patients with Hashimoto's thyroiditis may present with goiter rather than symptoms of hypothyroidism. It is usually irregular and firm in consistency . Hypothyroidism is less prominent clinically and better tolerated when there is a gradual loss of thyroid function (as in most cases of primary hypothyroidism) than when it develops acutely after thyroidectomy or abrupt withdrawal of exogenous thyroid hormone . The symptoms of central hypothyroidism are usually milder & less obvious than in primary hypothyroidism because of concurrent symptoms of coexisting hormone deficiencies. i.e. hot flashes due to hypogonadism may mask the cold intolerance of hypothyroidism.

24. HYPOTHYROIDISM CLINICAL MANIFESTATION MECHANISM SYMPTOMS SIGNS Slowing of metabolic processes Fatigue, weakness Cold intolerance Dypsnea on exertion Weight gain Mental retardation (infant) Constipation Growth Failure Slow movement and slow speech Delayed relaxation of tendon reflexes Bradycardia Carotenemia Accumulation of matrix substances Dry skin Hoarseness Edema Coarse skin Puffy facies and loss of eyebrows Periorbital edema Enlargement of the tongue Other Decreased hearing Myalgia and paresthesia Menorrhagia Arthralgia Pubertal delay Diastolic hypertension Pleural and pericardial effusions Ascites Galactorrhea

25. HYPOTHYROIDISM DEFFENRIATION BETWEEN PRIMARY AND SECONDARY HYPOTHYROIDISM

26. HYPOTHYROIDISM SKIN MANIFESTATION The skin is cool and pale in patients with hypothyroidism because of decreased blood flow. The epidermis has an atrophied cellular layer and hyperkeratosis that results in the characteristic dry roughness of the skin. Sweating is decreased because of decreases in calorigenesis and acinar gland secretion. A yellowish tinge may be present if the patient has carotenemia , while hyperpigmentation may be seen when primary hypothyroidism is associated with primary adrenal failure Hair may be coarse , hair loss is common, and the nails become brittle . Non-pitting edema (myxedema) occurs in severe hypothyroidism and may be generalized. It results from infiltration of the skin with glycosaminoglycans with associated water retention. Vitiligo and alopecia areata may be present in patients with hypothyroidism treatment of Graves‘ hyperthyroidism

27. HYPOTHYROIDISM

28. HYPOTHYROIDISM EYES MANIFESTATION Periorbital edema Thinning of outer third of eyebrows ( Madarosis ) Graves' ophthalmopathy may persist when hypothyroidism develops after treatment of Graves' hyperthyroidism HAEMATOLOGICAL MANIFESTATION Decrease in red blood cell mass Normochromic, normocytic hypoproliferative anemia Pernicious anemia occurs in 10 percent of patients with hypothyroidism caused by chronic autoimmune thyroiditis : macrocytic anemia with marrow megaloblastosis Women in the childbearing years may develop iron deficiency anemia , secondary to menorrhagia. In patients with IDA and hypothyroidism, combined therapy with levothyroxine and oral iron supplements results in correction of the anemia , which may be refractory to treatment with iron alone

29. HYPOTHYROIDISM CARDIOVASCULAR MANIFESTATION Decrease in cardiac output that is mediated by reductions in heart rate and contractility Thyroid hormone regulation of genes coding for specific myocardial enzymes involved in myocardial contractility and relaxation is responsible for the decrease in contractility . Reduced cardiac output probably contributes to decreased exercise capacity and shortness of breath during exercise. Hypercholesterolemia, which is caused by a decrease in the rate of cholesterol metabolism Diastolic Hypertension, because of an increase in peripheral vascular resistance. In normotensive patients, blood pressure increases are small (<150/100 ). ECG : Low voltage, sinus bradycardia, non-specific ST-T changes

30. HYPOTHYROIDISM RESPIRATORY MANIFESTATION Fatigue, shortness of breath on exertion, rhinitis, and decreased exercise capacity Hypoventilation occurs because of respiratory muscle weakness and reduced pulmonary responses to hypoxia and hypercapnia RESPIRATORY MANIFESTATION Decreased gut motility results in constipation Decreased taste sensation. Gastric atrophy due to the presence of anti-parietal cell antibodies Celiac disease is four times more common in hypothyroid patients Modest weight gain (despite poor appetite)due to decreased metabolic rate and accumulation of fluid

31. APPROACH HOW TO APPROACH PATIENT? HISTORY TAKING PHYSICAL EXAMINATION LAB INVESTIGATIONS

32. APPROACH INVESTIGATIONS – THYROID FUNCTION TEST

33. APPROACH INVESTIGATIONS – THYROID FUNCTION TEST NORMAL THYROID STIMULATING HORMONE - TSH FREE THYROXINE or FT4 NORMAL

34. HYPOTHYROIDISM MANAGEMENT Goal : Normalize TSH level regardless of cause of hypothyroidism Treatment of choice is thyroxine TSH should be measured at 6 to 8 weeks after any change in L-thyroxine brand or dose Determinants of Thyroxine Requirements: Age Severity and duration of hypothyroidism Weight Malabsorption Pregnancy Presence of cardiac disease Concomitant drug therapy

35. HYPOTHYROIDISM MANAGEMENT Starting dose for healthy patients <50 years should be at 1.6 mg/kg/day Starting dose for healthy patients >50 years should be <50 mg/day. Dose should be increased by 12.5-25 μg /day, if needed, at 6 to 8 weeks intervals. (Start low and go slow ) Starting dose for patients with heart disease should be 12.5 to 25 μg /day and increase by 12.5 to 25 μg /day, if needed, at 6 to 8 weeks intervals

36. HYPOTHYROIDISM CONDITIONS THAT ALTER LEVOTHYROXINE REQUIREMENTS

37. HYPOTHYROIDISM TREATMENT FOR SUBCLINICAL HYPOTHYROIDISM Refers to biochemical evidence of thyroid hormone deficiency in patients who have few or no apparent clinical features of hypothyroidism . Routine treatment not recommended when TSH levels are below 10 mU /L . Any elevation of TSH must be sustained over a 3-month period before treatment is given . Treatment is administered by starting with a low dose of levothyroxine (25–50 µg/d) with the goal of normalizing TSH. If thyroxine is not given, thyroid function should be evaluated annually . There is a risk that patients will progress to overt hypothyroidism, particularly when the TSH level is elevated and TPO antibodies are present.

38. HYPERTHYROIDISM

39. HYPERTHYROIDISM INTRODUCTION Hyperthyroidism is hyperactivity of thyroid gland with sustained increase in synthesis and release of thyroid hormones . Female Age more than 60 years old Smoking Have autoimmune disease Family history of thyroid disease or autoimmune disease History of goiter Past history of thyroid surgery Too much iodine intake through food or medication RISK FACTORS

40. HYPERTHYROIDISM AETIOLOGY Common causes of hyperthyroidism include : Grave disease Functioning adenoma and toxic multinodular goiter (TMNG) Excessive intake of thyroid hormones Abnormal secretion of TSH Thyroiditis Excessive iodine intake

41. HYPERTHYROIDISM PATHOPHYSIOLOGY

42. HYPERTHYROIDISM PATHOPHYSIOLOGY

43. HYPERTHYROIDISM PATHOPHYSIOLOGY

44. HYPERTHYROIDISM DISEASES IN HYPERTHYROIDISM Graves’ Disease Toxic multinodular Goiter Toxic adenoma

45. HYPERTHYROIDISM DISEASES IN HYPERTHYROIDISM Toxic multinodular Goiter Seen in the elderly and in iodine deficient areas. There are nodules that secrete thyroid hormones Compression symptoms such dysphagia or dyspnea Need surgery for the thyroid that keep on enlarge by removal the nodules Toxic Adenoma There is a solitary nodule producing T3 and T4 On isotope scan, the nodule is ‘hot’ and the rest of gland is suppressed

46. GRAVES’ DISEASE INTRODUCTION Also known as toxic diffuse goiter , is an autoimmune disease that affects the thyroid, presented with enlarged thyroid. It is the most common cause of hyperthyroidism. Idiopathic causes : Family history of grave disease Genetic factors Triggered by stress, infection Autoimmune disease (type 1 DM, Addison’s disease) Smoking

47. GRAVES’ DISEASE PATHOGENESIS Circulating IgG autoantibodies directed against the thyrotropin receptor binding to and activating G-protein-coupled thyrotropin receptors, which cause smooth thyroid enlargement . This cause increase hormone production especially T3. React with orbital auto-antigens. Triggers with stress and infection.

48. PATHOGENESIS

49. GRAVES’ DISEASE PATHOGENESIS Production of thyroid hormones is regulated by TSH. The binding of TSH to a receptor on thyroid cells activates adenylate cyclase and stimulates the synthesis of 2 thyroid hormones : T3 & T4 A person with Grave’s disease makes auto-antibodies to the receptor for TSH. The binding of these auto-antibodies to the receptor mimics the normal action of TSH, without the regulation, leading to overstimulation of the gland. The auto-antibodies are called long acting TSH.

50. GRAVES’ DISEASE HOW TO APPROACH PATIENT ? History Taking Physical Examination WHAT TO INCLUDE IN HISTORY TAKING? Unexplained weight loss even with good appetite Excessive sweating especially at night Cannot tolerance to heat Excitability, irritability, tremulousness Palpitations Any pressure symptoms such as dysphagia, dyspnea and hoarseness of voice Family history of hyperthyroidism History of autoimmune disease History of goiter and past thyroid surgery History of iodine contrast media use Smoking or not Iodine intake history either medication or diet

51. GRAVES’ DISEASE CLINICAL FEATURES

52. GRAVES’ DISEASE CLINICAL FEATURES SYMPTOMS Palpitation , tremor, heat intolerance, sweating, increase appetite and unintentional weight loss Eye symptoms (30-50%) : exophthalmos, opthalmoplagia Thyroid dermopathy : Pretibial myxedema (7%) Thickening of the skin, particularly over the lower tibia due to accumulation of glycosaminoglycan Thyroid A cropachy - Clubbing of fingers (rare)

53. GRAVES’ DISEASE HOW TO APPROACH PATIENT ? History Taking Physical Examination WHAT TO LOOK FOR IN PHYSICAL EXAMINATION? Unilateral neck swelling or goiter usually with or without bruit in grave disease (describe the swelling) Proximal muscle weakness Hyperreflexia Warm and sweaty palms Palmar erythema Fine finger tremors Lid retraction, lid lag, exophthalmos Resting tachycardia

54. GRAVES’ DISEASE CLINICAL FEATURES

55. INVESTIGATION Full blood count – Hemoglobin ( Hb ) and Total White Count (TWC) to rule out sign of infection Thyroid function test – TSH, T3 and T4 Serum thyroid autoantibodies Serum calcitonin level Serum thyroglobulin level Isotopes scan Radioactive iodine uptake and scan – to rule out thyroiditis Thyroid ultrasound + Colour flow Doppler Ultrasound Inhomogeneous diffusely hypoechoic gland Colour Doppler Hypervascular – Thyroid inferno

56. LAB INVESTIGATION THYROID FUNCTION TEST

57. LAB INVESTIGATION

58. LAB INVESTIGATION SUMMARY

59. GRAVES’ DISEASE HOW TO MANAGE THIS PATIENT? Three forms of therapy are available : Medical Treatment Anti-thyroid drug Thionamides ( carbimazole or propylthiouracil ) are the commonest forms of treatment that can be used for most patients with the hope of achieve long term remission. Also used in preparation for surgery and radioiodine therapy B- blockers For symptoms relief initially Propranolol 30-120mg/day

60. GRAVES’ DISEASE HOW TO MANAGE THIS PATIENT? Anti-thyroid drug most useful in : Children It is effective and more acceptable to patients Pregnancy The doses should lower as possible to reduce risk of fetal goiter. PTU is preferred to carmibazole in pregnancy and breastfeeding time Patient with medical complications Thyroid crisis and heart failure Patient who contraindicated to surgery or refuse surgery Patient who relapse after thyroidectomy

61. GRAVES’ DISEASE HOW TO MANAGE THIS PATIENT?

62. GRAVES’ DISEASE HOW TO MANAGE THIS PATIENT? Surgery Thyroidectomy Indication : Failed medical treatment; relapse after one and non compliance to anti thyroid drug With large goiters and pressure symptoms Radioiodine therapy Contraindicated in pregnant and breastfeed mother

63. THYROIDITIS

64. INTRODUCTION Thyroiditis is inflammation of the thyroid gland with destruction of the thyroid tissues to a variable degree. The presentation, functional disturbance and prognosis depend on the aetiology of the thyroiditis. Presentation may be acute, subacute or chronic. The causes are : Autoimmune – Hashimoto’s thyroiditis, Post-partum thyroiditis & Atrophic thyroiditis Infection – Viral thyroiditis (De Quervain’s thyroiditis) Physical – Radiation to the neck Idiopathic – Painless thyroiditis, Riedel’s thyroiditis

65. THYROIDITIS TYPES Hashimoto’s thyroiditis presents with diffuse firm goitre . Patients are usually euthyroid but may develop hypothyroidism in the long term. Few patients may present with thyrotoxicosis due to co-existing Graves’ disease. It is more common in females in the fourth and fifth decades. There is often a positive family history of goitre or other autoimmune diseases. HASHIMOTO’S THYROIDITIS

66. THYROIDITIS TYPES Postpartum thyroiditis is an autoimmune disorder presenting with thyrotoxicosis followed by euthyroid and hypothyroid phases a few months after delivery. A proportion of patients may present at the hypothyroid phase. Unlike De Quervain’s , there is no pain in the thyroid which is enlarged in about 50% of cases. The thyrotoxic phase lasts for about 2 months but the hypothyroid phase may last for 2-9 months. About 5% of the patients develop permanent hypothyroidism. POSTPARTUM THYROIDITIS PAINLESS THYROIDITIS Painless thyroiditis is of unknown aetiology and is similar to postpartum thyroiditis except that this is not associated with pregnancy.

67. THYROIDITIS TYPES Subacute (De Quervain's ) thyroiditis usually presents with pain in the region of thyroid gland which may be mistaken for pharyngitis accompanied in severe cases by fever . Patient may presented with fatigue , difficulty in swallowing and may also came with accompanying symptoms and signs of thyrotoxicosis . On palpation, the gland is slightly to moderately enlarged , firm and usually exquisitely tender . The disease usually passes through a euthyroid phase followed by a transient hypothyroid phase prior to full recovery within a few months in the majority of cases. Rarely , permanent hypothyroidism may result . DE QUERVAIN’S THYROIDITIS

68. THYROIDITIS TYPES Riedel’s thyroiditis is a rare condition of unknown aetiology presenting with hypothyroidism and woody hard goitre . The extensive fibrosis may involve the adjacent structures e.g. trachea and oesophagus and may be associated with fibrosis elsewhere especially in the retroperitoneal area. Some patients may have elevated anti-thyroid antibodies but not as high as those of Hashimoto’s thyroiditis. RIEDEL’S THYROIDITIS

69. THYROIDITIS TYPES Acute pyogenic thyroiditis is rare and is usually a result of dissemination from a septic focus elsewhere. It usually presents with fever , pain and signs of acute inflammation in the thyroid gland . Needle aspiration of the thyroid should be performed for diagnosis and identification of the organism. Rarely , tuberculosis or anaplastic carcinoma of the thyroid may present similarly. ACUTE PYOGENIC THYROIDITIS

70. THYROIDITIS LAB INVESTIGATIONS Thyroid function tests T o assess functional status are indicated in all patients with thyroiditis since some may have subclinical thyroid dysfunction. Repeat measurements should be performed as thyroid status may change . Other tests to confirm aetiology includes: T hyroid autoantibodies (anti-thyroid peroxidase and anti-thyroglobulin ) T hyroid aspirate (FNAC) for cytological diagnosis and culture in the case of pyogenic thyroiditis. Isotope uptake scan is useful in differentiating thyrotoxicosis due to thyroiditis from Graves’ disease. ESR is raised in De Quervain’s thyroiditis and useful in monitoring activity of the disease.

71. THYROIDITIS MANAGEMENT NSAIDs to relieve pain. In De Quervain’s thyroiditis , if pain persists after 1 week of NSAIDs treatment , steroid therapy (prednisolone 30 mg/day for 1 week) is useful. Antithyroid drugs (e.g. carbimazole ) are not indicated . Beta-blockers may be useful to alleviate symptoms .

72. THYROIDITIS MANAGEMENT L-thyroxine is indicated for hypothyroidism. It may be withdrawn after 6-12 months in postpartum or painless thyroiditis to determine whether there is recovery of thyroid function. In Hashimoto’s thyroiditis, hypothyroidism is likely to be permanent and patients require life-long thyroid hormone replacement. Antibiotics are indicated in pyogenic thyroiditis . Surgical drainage may be required.

73. THYROID EMERGENCIES

74. INTRODUCTION THYROID EMERGENCIES In the USA, the overall incidence of hyperthyroidism is estimated to be between 0.05% and 1.3%, with the majority of cases being subclinical in terms of presentation. Among hospitalized thyrotoxicosis patients, the incidence of thyroid storm has been noted to be <10 %. The mortality of thyroid storm without treatment ranges between 80% and 100%; with treatment, this figure is between 10% and 50%. Multiple organ failure was reported to be the most common cause of death in thyroid storm .

75. TYPES THYROID EMERGENCIES MYXEDEMA COMA THYROID STORM Thyroid storm represents the extreme presentation of thyrotoxicosis. An extreme complications of hypothyroidism in which patients exhibit multiple organ abnormalities and progressive mental deterioration. Occurs when the body’s compensatory responses to hypothyroidism are overwhelmed by various precipitating stressors . Myxedema coma is used to describe the severe life-threatening manifestations of hypothyroidism . The term myxedema coma itself is a misnomer, as patients do not usually present with frank coma but more commonly have altered mental status or mental slowing. Myxedema actually refers to the non-pitting puffy appearance of the skin and soft tissues related to hypothyroidism

76. MYXEDEMA COMA COMMON PRECIPITATING FACTORS MYXEDEMA COMA INFECTIONS STRESS HYPOVOLEMIA DRUGS Pneumonia UTI Sedative & Tranquilizers Amiodarone Lithium Narcotics Diuretics Anaesthesia Example : GI Bleeding, Surgery Stroke Acute MI Trauma

77. MYXEDEMA COMA PATHOPHYSIOLOGY

78. MYXEDEMA COMA CLINICAL FEATURES P rimarily a clinical diagnosis with features of uncomplicated hypothyroidism but more exaggerated . Thyroid hormone levels are similar to those found in uncomplicated hypothyroidism. Female at risk Elderly Positive symptoms and signs of hypothyroidism – Look for thyroidectomy scar or features of hypopituitarism : Hypothermia Hypotension, bradycardia Hypoventilation Hyporeflexia

79. MYXEDEMA COMA CLINICAL FEATURES The cardinal features of myxedema coma are: H ypothermia , which can be profound Altered mental status – Confusion, Delirium, Psychosis, Fit, Coma Cardiovascular depression The severely hypothyroid patient essentially becomes poikilothermic due to disordered thermoregulation. This is the reason many cases occur in the winter months. Body temperatures as low as 23.3°C have been reported; thus, rectal temperatures are essential to making the diagnosis .

80. MYXEDEMA COMA DIAGNOSTIC CRITERIA – JOHN HOPSKIN

81. MYXEDEMA COMA DIAGNOSTIC CRITERIA – JOHN HOPSKIN

82. MYXEDEMA COMA LAB INVESTIGATIONS Full Blood Count –Total White Count and Hb level (Macrocytic Anemia) BUSE – Hyponatremia (usually like SIADH – like picture) Liver Function Test – Elevated transaminases ABG test – Hypercapnia and Hypoxia Lipid profile – Hyperlipidemia Thyroid Function Test Blood C&S – To rule out infections Urine Analysis – microscopic hematuria, leukocytes Urine C&S BED SIDE INVESTIGATIONS ECG – Abnormal ECG: Prolonged PR, QRS and QT, abnormal T wave and arrhythmias . Random Blood Sugar test – Hypoglycemia IMAGING Chest Xray – Pericardial effusion ± pleural effusion

83. MYXEDEMA COMA

84. MYXEDEMA COMA MANAGEMENT Treatment should be started on clinical grounds. If in genuine doubt, it is worth treating as myxedema coma, as giving L- tyroxine judiciously is unlikely to be harmful in the short term. Ideally patient should be managed in ICU. Thyroid hormone replacement Replacement therapy should be gentle if patients are elderly and at risk of cardiac arrhythmias, heart failure or myocardial ischemia. Whether T3 or T4 or both should be given is controversial. Reason: T3 is has faster onset of action and is the active hormone. T4 has a much longer half-life, more gradual onset of action and is converted to T3 endogenously. Use of T4 avoids a sudden rise in active T3, which may have adverse cardiac effects in patients at risk. However, conversion T4  T3 may be impaired in critically ill patient.

85. MYXEDEMA COMA MANAGEMENT Reason: Oral T4 has variable oral bioavailability of 40-80%. Avoid co-administration with antacid, calcium or iron supplement. In contrast oral T3 has almost 100% oral bioavailability even in hypothyroid patient. If ischemic heart disease is suspected, dosages of both the above should be halved. T4 IV 200 – 500 µg bolus or oral by NG tube followed by daily dose of 50 – 100 µg until patient can take orally. (Oral T4 may be given if T3 or IV T4 is not available but the action is too slow) T3 IV or oral by NG tube 10 – 20 µg 8 – 12 hourly until T4 can be given orally.

86. MYXEDEMA COMA MANAGEMENT Steroids All patients should be given 100 mg hydrocortisone IV stat and then 50 – 100 mg 6 – 8 hourly until adrenal insufficiency (due to Addison’s disease or hypothyroidism) has been ruled out. Ventilation If Pa02 is <60 mmHg with O2 or if PaCO2 is >60 mmHg, assisted ventilation may be required. Treat accordingly : Hypothermia Passive external rewarming. Do not warm the patient rapidly as this may cause cardiovascular collapse. Use a lots of blankets and monitor the rectal temperature. Do not correct faster than 1°C/Hour.

87. MYXEDEMA COMA MANAGEMENT Hypothermia A low reading thermometer should be used. Give warm humidified oxygen by facemask. Hypoglycemia Should be corrected Exclude concurrent adrenal or pituitary insufficiency. Hyponatremia Usually resolved with thyroxine replacement and careful attention to fluid status. If Na <110 mmol /L, hypertonic saline may be given, with a maximal correction of serum sodium by not more than 10 mmol /24 hour period.

88. MYXEDEMA COMA Cardiovascular Myxedema patients have: Reduction in total blood volume due to chronic vasoconstriction to preserve body core temperature Depressed cardiac function and reduced responsiveness to catecholamine . Hence, they tolerate further volume loss (in GI bleed, diuretic, vasodilation due to sepsis or rapid rewarming) poorly resulting in hypotension. If necessary, plasma expanders or blood products should be given cautiously guided by CVP. Cardiac monitor for supraventricular arrhythmias. Remove or treat precipitating causes. Cover with IV antibiotic if in doubt . Monitor rectal temperature, oxygen saturation, BP, CVP and urine output . On full recovery , doses of replacement thyroxine should be titrated to maintain an euthyroid state .

89. THYROID STORM INTRODUCTION Thyroid storm also referred to as thyrotoxic crisis, is an acute , life threatening hypermetabolic state induced by excessive release of TSH in individuals with thyrotoxicosis. It is a decompensated state of thyroid hormone - involving multiple systems and is the most extreme state of thyrotoxicosis . The condition is rare, however, mortality rates are high and may approach 10-20%. PERCIPITATING FACTORS Infections Surgery Poorly prepared thyroid surgery Diabetic ketoacidosis Radioiodine therapy in poorly prepared patient Trauma Myocardial Infarction Drug : Amiodarone Discontinuation of anti-thyroid drugs Labour

90. THYROID STORM PATHOPHYSIOLOGY The detailed pathophysiology is not fully understood , but it is thought to be related to increased numbers of beta-adrenergic receptors being exposed to increased catecholamine levels in states of stress . UNDERLYING CAUSES OF THYROTOXICOSIS THAT PREDISPOSE TO THYROID STORM Graves’ Disease Solitory toxic adenoma Thyroid carcinoma TSH – secreting pituitary adenoma Hyadatiform mole Iodine exposure (IV radiocontrast dye, amiodarone)

91. THYROID STORM CLINICAL FEATURES Diagnosis is primarily clinical based on high index of suspicion and there are several factors may precipitate the progression of thyrotoxicosis to thyroid storm. Thermoregulatory : High fever, sweating CNS dysfunction : Agitation, confusion, acute psychosis, coma Cardiovascular : Tachycardia, AF, heart failure GIT : Diarrhea and vomiting, acute abdominal pain, jaundice and hepatic dysfunction. The combination sign and symptoms makes the diagnosis of thyroid storm, and to produce scoring systems to improve diagnostic accuracy . Burch- Wartofsky point scale Japan Thyroid Association categories of thyroid storm 2012 Scoring system must not be used among patients without severe thyrotoxicosis.

92. THYROID STORM DIAGNOSITIC CRITERIA – BURCH-WARTOFSKY POINT SCALE

93. THYROID STORM DIAGNOSITIC CRITERIA – BURCH-WARTOFSKY POINT SCALE

94. THYROID STORM JAPAN THYROID ASSOCIATION CATEGORIES OF THYROID STORM

95. THYROID STORM INVESTIGATIONS Full Blood Count – Total white count, Hemoglobin level BUSE – dehydration status Blood Glucose - Hypoglycemia Liver Function Test Thyroid Function Test Other additional test to investigate the precipitants PERCIPITATING FACTORS Infections Diabetic ketoacidosis Myocardial Infarction

96. THYROID STORM MANAGEMENT Mortality of untreated storm is high; if the diagnosis is suspected, anti-thyroid treatment must be started before biochemical confirmation. Ideally patient should be managed in ICU. Hyperthyroidism Inhibition of thyroid hormone formation : Propylthiouracil (PTU) Carbimazole Loading dose 600 mg stat and 90-1200 mg/day orally OR NG tube in 4-6 divided doses ( e.g 200 mg 4 hourly reduced to 100-200 mg, 6-8 hourly after 24-48 hour) PTU may be preferable to Carbimazole as it has the additional action of inhibiting peripheral conversion of T4 to T3. 60-120 mg/day in 3-4 divided doses orally or NG tube

97. THYROID STORM MANAGEMENT

98. THYROID STORM MANAGEMENT Hyperthyroidism Inhibition of thyroid hormone release : SODIUM IODIDE IV 1 g/24 hour by slow infusion ORAL POTASSIUM IODIDE 100 mg 6 hourly OR ORAL LUGOL’S IODINE 10 – 20 drops 8 hourly OR Iodine should be given at least one hour after the patient has received the initial dose of PTU or carbimazole ; this is to ensure that the iodine given is not taken up by the gland for further thyroid hormone synthesis and release.

99. THYROID STORM MANAGEMENT Steroids IV dexamethasone 2 mg 6 hourly . Dexamethasone inhibits both release of thyroid hormones and peripheral conversion of T4 to T3. Receptors blockade (in the absence of heart failure) PROPANOLOL IV Propanolol 1-2 mg slowly 4-6 hourly OR Oral propranolol 40-60 mg 6 hourly Should not be used if there is pulmonary or peripheral oedema and if heart failure supervenes , atropine 0.4-1 mg IV should be given. Assessment of LV function will help guide the use of beta-blockers.

100. THYROID STORM MANAGEMENT Receptors blockade (in the absence of heart failure) Diltiazem 60-120 mg 6 hourly Pulmonery Oedema can be used if beta blockade is contraindicated e.g bronchial asthma. IV Esmolol May be useful in difficult case to allow rapid titration due to its short half life. Cardiac Failure Usually associated with fast AF Diuretics, digoxin, oxygen as appropriate and propranolol if cardiac failure is due to uncontrolled AF and LV function is good. There is relative digoxin resistance with increased renal excretion and decreased action on AV conduction, so a higher dose of digoxin may be needed. Cardioversion of AF is very unlikely to be successful and should wait until patient is euthyroid and Amiodarone may be useful when given parentally to control acute arrhythmias.

101. THYROID STORM MANAGEMENT Hyperpyrexia Fans, tepid sponge, and paracetamol. Dehydration Cautious replacement of fluid. CVP line is helpful. Anticoagulation Give heparin by infusion in patients with AF. Other patients should receive SC heparin 5000U 2 times daily or LMWH as prophylaxis against venous thromboembolism. Remove or treat precipitating factors Exchange transfusion of Peritoneal Dialysis/Hemodialysis This may be considered in patient who is resistant to the usual pharmacological measures.

102. MANAGEMENT

103. MYXEDEMA VS THYROID STORM

104. REFERENCES Harrison’s Principles of internal medicine – 18th Edition Sarawak Handbook of Medical Emergencies 3 rd Edition Malaysian CPG 2000 UpToDate.com Publications from the American Thyroid Association, American Association of Clinical Endocrinologists, and the Endocrine Society National Center for Biotechnology Information [https ://www.ncbi.nlm.nih.gov/pmc/articles/PMC5667251 /]