Thyrotoxicosis

thyrotoxicosis

1. Thyrotoxicosis By HALLIDAY, C.A

2. INTRODUCTION EPIDEMIOLOGY AETIOLOGY PATHOPHYSIOLOGY CLINICAL FEATURES DIAGNOSIS MANAGEMENT COMPLICATIONS FOLLOW UP PROGNOSIS CONCLUSION REFERENCE

3. Introduction T hyrotoxicosis is defined as the state of thyroid hormone excess and is not synonymous with hyperthyroidism, which is the result of excessive thyroid function. However, the major etiologies of thyrotoxicosis are hyperthyroidism caused by Graves’ disease, toxic multinodular goiter (MNG), and toxic adenomas.

4. Epidemiology All thyroid diseases occur more frequently in women than in men. Graves autoimmune disease has a male-to-female ratio of 1:5-10. The male-to-female ratio for toxic multinodular goiter and toxic adenoma is 1:2-4. Graves ophthalmopathy is more common in women than in men. Autoimmune thyroid diseases have a peak incidence in people aged 20-40 years.

5. Thyroid Physiology Iodine Metabolism: The average daily iodine requirement is 0.1 mg. •Sources : Fish, milk, and eggs or as additives in bread or salt. • In the stomach and jejunum, iodine is rapidly converted to iodide and absorbed into the bloodstream. • Iodide is actively transported into the thyroid follicular cells by an adenosine triphosphate (ATP)– dependent process. • The thyroid is the storage site of >90% of the body's iodine content

6. Thyroid Hormone synthesis Iodide trapping, involves active (ATP-dependent) transport of iodide across the basement membrane of the thyrocyte via an intrinsic membrane protein, the sodium/iodine (Na+/I–) symporter . Oxidation of iodide to iodine and iodination of tyrosine residues on Tg , to form monoiodotyrosines (MIT) and diiodotyrosines (DIT ). Coupling of two DIT molecules to form tetraiodothyronine or thyroxine (T4 ), and one DIT molecule with one MIT molecule to form 3,5,3'triiodothyronine (T3). Thyroglobuin ( Tg ) is hydrolyzed to release free iodothyronines (T3 and T4) and mono- and diiodotyrosines by stimulation of TSH and engulfing within thyroid follicle. The latter are deiodinated in the fifth step to yield iodide, which is reused in the thyrocyte .

7. In the euthyroid state, T4 is produced and released entirely by the thyroid gland, whereas only 20% of the total T3 is produced by the thyroid. • Most of the T3 is produced by peripheral deiodination (removal of 5'-iodine from the outer ring) of T4 in the liver, muscles, kidney, and anterior pituitary, a reaction that is catalyzed by 5'-mono-deiodinase. • Thyroid hormones are transported in serum bound to carrier proteins such as T4-binding globulin, T4-binding prealbumin , and albumin.

8. Only a small fraction (0.02%) of thyroid hormone (T3 and T4) is free (unbound) and is the physiologically active component. • T3 is the more potent of the two thyroid hormones, although its circulating plasma level is much lower than that of T4. • T3 is three to four times more active than T4 per unit weight, with a half-life of about 1 day, compared to approximately 7 days for T4.

9. The thyroid gland also is capable of autoregulation , which allows it to modify its function independent of TSH. • As an adaptation to low iodide intake, the gland preferentially synthesizes T3 rather than T4 , thereby increasing the efficiency of secreted hormone. • In situations of iodine excess, iodide transport, peroxide generation, and synthesis and secretion of thyroid hormones is inhibited. • Excessively large doses of iodide may lead to initial increased organification , followed by suppression, a phenomenon called the WolffChaikoff effect.

10. CAUSES OF THYROTOXICOSIS Primary Hyperthyroidism 1. Graves’ disease 2. Toxic multinodular goiter 3. Toxic adenoma 4. Functioning thyroid carcinoma metastases 5. Activating mutation of the TSH receptor 6. Struma ovarii 7. Drugs: iodine excess ( Jod-Basedow phenomenon)

11. Thyrotoxicosis Without Hyperthyroidism 1. Subacute thyroiditis 2. Silent thyroiditis 3. Other causes of thyroid destruction: amiodarone , radiation, infarction of adenoma 4. Ingestion of excess thyroid hormone (thyrotoxicosis factitia ) or thyroid tissue Secondary Hyperthyroidism 1. TSH-secreting pituitary adenoma 2. Chorionic gonadotropin-secreting tumors 3. Gestational thyrotoxicosis

12. Diffuse toxic goitre(Grave’s disease) Graves’ disease accounts for 60–80% of thyrotoxicosis. It is an autoimmune disease with a strong familial predisposition, female preponderance (5:1). • Peak incidence between the ages of 40 to 60 years. • Graves' disease is characterized by thyrotoxicosis, diffuse goiter, and extrathyroidal conditions including ophthalmopathy , dermopathy (pretibial myxedema), thyroid acropachy , gynecomastia , and other manifestations.

13. Etiology and Pathogenesis The exact etiology of the initiation of the autoimmune process in Graves' disease is not known. A combination of environmental and genetic factors contribute to Graves’ disease susceptibility. Genetic factors, including polymorphisms in HLA-B8 and HLA-DR3 and HLADQA1*0501. cytotoxic T-lymphocyte-associated protein 4, CD25, PTPN22, Fc receptor-like3, and CD226, as well as the TSH-R, Smoking, Sudden increases in iodine intake• Postpartum state, lithium therapy, and bacterial infections have been suggested as possible triggers.

14. Stimulate B lymphocytes, which produce antibodies directed against the thyroid hormone receptor. • TSIs or antibodies that stimulate the TSH-R, as well as TSH-binding inhibiting immunoglobulins or antibodies have been described. • The thyroid-stimulating antibodies stimulate the thyrocytes to grow and synthesize excess thyroid hormone, which is a hallmark of Graves' disease. • Graves' disease also is associated with other autoimmune conditions such as type I diabetes mellitus, Addison's disease, pernicious anemia , and myasthenia gravis.

15. Toxic Multinodular Goiter ( Plummers Disease) MNG occurs in up to 12% of adults. More common in women than men and increases in prevalence with age. It is more common in iodine deficient regions

16. Toxic Adenoma A solitary, autonomously hyperfunctioning thyroid nodule- Toxic Adenoma. • Thyrotoxicosis is usually mild. • Suggested by the presence of the palpable thyroid nodule & by the absence of clinical features suggestive of Graves' disease or other causes of thyrotoxicosis

17. Pathophysiology The secretion of thyroid hormone is controlled by a complex negative feedback mechanism involving the interaction of stimulatory and inhibitory factors. Thyrotropin -releasing hormone (TRH) from the hypothalamus stimulates the pituitary to release TSH.

18. Binding of TSH to receptors on the thyroid gland leads to the release of thyroid hormones—primarily T4 and to a lesser extent T3. In turn, elevated levels of these hormones act on the hypothalamus to decrease TRH secretion and thus the synthesis of TSH.

19. Synthesis of thyroid hormone requires iodine. Dietary inorganic iodide is transported into the gland by an iodide transporter, converted to iodine, and bound to thyroglobulin by the enzyme thyroid peroxidase through a process called organification . This results in the formation of monoiodotyrosine (MIT) and diiodotyrosine (DIT), which are coupled to form T3 and T4; these are then stored with thyroglobulin in the thyroid’s follicular lumen. The thyroid contains a large supply of its preformed hormones.

20. Thyroid hormones diffuse into the peripheral circulation. More than 99.9% of T4 and T3 in the peripheral circulation is bound to plasma proteins and is inactive. Free T3 is 20-100 times more biologically active than free T4. Free T3 acts by binding to nuclear receptors (DNA-binding proteins in cell nuclei), regulating the transcription of various cellular proteins. Any process that causes an increase in the peripheral circulation of unbound thyroid hormone can cause thyrotoxicosis

21. CLINICAL MANIFESTATIONS The clinical presentation depends on :- the severity of thyrotoxicosis, the duration of disease, individual susceptibility to excess thyroid hormone, and the patient’s age.

22. In the elderly, features of thyrotoxicosis may be subtle or masked, and patients may present mainly with fatigue and weight loss, a condition known as apathetic thyrotoxicosis.

23. Symptoms Signs 1. Hyperactivity, irritability, dysphoria 2. Heat intolerance and sweating 3. Palpitations 4. Fatigue and weakness 5. Weight loss with increased appetite 6. Diarrhea 7. Polyuria 8. Oligomenorrhea , loss of libido 9. Insomina 1. Tachycardia; atrial fibrillation in the elderly 2. Tremor 3. Goiter 4. Warm, moist skin 5. Muscle weakness, proximal myopathy 6. Lid retraction or lag 7. Gynecomastia

24. Neurologic manifestations include : Nervousness, irritability, emotional lability , psychosis, fine tremors, hyper- reflexia , ill-sustained clonus muscle wasting, proximal myopathy without fasciculation, Chorea is rare.

25. Cardiovascular manifestation : Sinus tachycardia(M/C), Atrial fibrillation (>50 years of age), Angina, Palpitations, bounding pulse, Wide pulse pressure, aortic systolic murmur, Supraventricular tachycardia, CHF, Cardiomyopathy

26. Gastrointestinal manifestations include – Weight loss, Thyrotoxicosis cause unexplained weight loss, despite an enhanced appetite, due to the increased metabolic rate. Weight gain occurs in 5% of patients, because of increased food intake. increased appetite, vomiting, increased stool frequency, diarrhoea, steatorrhoea

27. Reproductive manifestations include – Menstrual disturbances (amenorrhoea or oligomenorrhoea ), infertility, repeated abortions loss of libido Impotence Gynaecomastia

28. Graves’ ophthalmopathy . Onset :- within the year before or after the diagnosis of thyrotoxicosis in 75% of patients Earliest manifestations sensation of grittiness, eye discomfort, and excess tearing. Proptosis , Periorbital edema , chemosis , diplopia, compression of the optic nerve at the apex of the orbit

29. Eye Signs in Hyperthyroidism : Von Graefe’s — Lid lag, Joffroy’s —Absence of wrinkling of forehead on looking up Stellwag’s — Decreased frequency of blinking Dalrymple’s — Lid retraction exposing the upper sclera Moebius sign : Inability or failure to converge the eye balls Gifford's sign: Difficulty in eversion of the upper lid

30. Grading of eye changes : “NO SPECS” 0 = No signs or symptoms 1 = Only signs (lid retraction or lag), no symptoms 2 = Soft tissue involvement ( periorbital edema ) 3 = Proptosis (>22 mm) 4 = Extraocular muscle involvement (diplopia) 5 = Corneal involvement 6 = Sight loss d/t optic nerve involvement

31. Dermatological manifestations include : Increased sweating, warm and moist skin, Diffuse alopecia, pruritus, palmar erythema spider naevi , onycholysis , Pretibial myxedema , Thyroid acropachy

32. Thyroid • Usually diffusely enlarged to >2–3 times its normal size. • The consistency is firm. • Thrill or bruit- increased vascularity of the gland and the hyperdynamic circulation.

33. DIAGNOSIS Tests of Thyroid Function Serum Thyroid-Stimulating Hormone (Normal 0.5–5 U/mL): Serum TSH levels reflect the ability of the anterior pituitary to detect free T4 levels. Small changes in free T4 lead to a large shift in TSH levels (Inverse relation). Total T4 (Reference Range 55–150 nmol /L) and T3 (Reference Range 1.5–3.5 nmol /L). Free T4 (Reference Range 12–28 pmol /L) and Free T3 (3–9 pmol /L). Thyroid Antibodies : Thyroid antibodies include antiTg , antimicrosomal , or anti-TPO and thyroidstimulating immunoglobulin (TSI).

34. Diagnosis TSH Assay- s ingle best test of Thyroid Hormone action at cellular level. Subclinical hyperthyroidism - TSH level is 0.10.4mU/L with normal FT3 & FT4. Overt hyperthyroidism - TSH level is <0.03mU/L with increased T3 & T4. Thyroid Storm - TSH level is <0.01mU/L. Free T4 (FT4 )- approx 0.02% of total T4. Elevated in 90% of patients with hyperthyroidism. Decreased in 85% of patients with hypothyroidism.

35. Radioactive iodine uptake I123, I131 & Tc99 - Varies directly with functional state of thyroid. - 24 hr thyroid uptake is measured. - Normal value range – 10-25% - Used to confirm Hyperthyroidism.

36. Thyroid scan using I123 or Tc99 evaluate nodules as - Warm / Normal - Hot / Hyperfunctioning . - Cold / Hypofunctioning Ultrasonography to differentiate between cystic, mixed or solid lesion in gland.

37. Thyroid USS a diffusely abnormal-appearing thyroid gland; it is enlarged, heterogeneous and hypoechoic . The Doppler image on the right shows diffusely increased vascularity throughout the thyroid. This appearance is called a ‘thyroid inferno’. These are the typical sonographic features of Graves disease.

38. T3 resin uptake test (RT3U)- Indirect measure of unbound fraction of T4. • It quantitates the degree of saturation of TBG sites by T3 & T4. • It is directly proportional to FT4 & inversely proportional to TBG sites. FT4 index = T4 x RT3U. Normal value- 1.4-4.9 In 2–5% of patients, only T3 is increased (T3 toxicosis ). The converse state of T4 toxicosis - hyperthyroidism is induced by excess iodine.

39. TRH stimulation test  used to test pituitary function. • Measurement of TPO antibodies is useful in differential diagnosis. • Measurement of TBII or TSI will confirm the diagnosis but is not needed routinely.

40. Other tests Serum Antimicrosomal Antibodies -Anti- Tg and anti-TPO antibodies are elevated in up to 75% of patients. Antithyroglobulin antibodies- elevated TSH-R or thyroid-stimulating antibodies ( TSAb ) are diagnostic of Graves' disease and are increased in about 90% of patients. Long acting thyroid stimulators (LATS). Thyroglobulin, is a protein made by cells in the thyroid. mostly used as a tumor marker test to help guide thyroid cancer treatment. Occasionally ordered to help determine the cause of hyperthyroidism and to monitor the effectiveness of treatment for conditions such as Graves disease

41. Other Investigations Complete blood count, to rule out anaemia, thrombocytopenia and agranulocytosis . • Urinalysis- Albumin, Sugar, Microscopy • RBS, Serum creatinine /u/e • ECG- Sinus tachycardia, ST elevation, QT shortening, atrial fibrillation/flutter, ventricular ectopic

42. Chest X-ray PA view- position of trachea, deviation, retrosternal goiter, calcification. Lateral view and barium swallow- pressure effects on trachea and oesophagus

43. Flow volume loop- best indications of airway obstruction. CT scan and MRI scan-for airway evaluation and extension of thyroid

44. Treatment Medical therapy Radioiodine ablation Surgery For the medical therapy, there are two types of regimen; Titration regimen Block and replace regimen

45. Antithyroid drugs Carbimazole (CBZ), Methimazole , propylthiouracil (PTU) belonging to the thioureas group • also blocks the conversion of T4 to T3 in the peripheral tissues. PTU is started at a dose of 100 mg • CBZ at a dose of 10 to 20 mg thrice daily. Most patients become euthyroid within 4 to 8 weeks of therapy. The dose is then reduced to a maintenance dose.

46. Iodides It is the fastest acting thyroid inhibitor. It reduces iodide transport, oxidation and organification and to block the release of T4 and T3 from the thyroid gland. The preparations used include Lugol's iodine (3 to 5 drops thrice daily). 5% sol has 5% iodine and 10% pot iodide. The major use of iodide is in preoperative preparation and in the management of thyrotoxic storm

47. Beta-blockers block beta-adrenergic receptors and provide relief from symptoms like tremors, palpitations, anxiety and heat intolerance. • decrease the heart rate, cardiac output and oxygen consumption in thyrotoxicosis. • The drugs used are propranolol (40 to 180 mg/day) or atenolol (25 to 100 mg/day). • contraindicated in patients with congestive cardiac failure, asthma

48. Radioiodine Therapy Radioiodine is simple and economical therapy. Indicated in patients above 40 years, especially those who fail to respond to antithyroid drugs and failures of surgery. Contraindicated during pregnancy and lactation and in severe thyrotoxicosis or in patients with large or malignant thyroids. A dose that will deliver about 5,000 to 8000 rads to the thyroid will be effective in ameliorating the hyperthyroidism in Graves' disease. The patients should be euthyroid prior to radioiodine therapy to prevent thyroid storm. The main drawbacks are hypothyroidism, risk of carcinogenesis, and teratogenicity after the use of radioiodine, though the precise likelihood of the latter two remain contentious.

49. Diet No special diet must be followed by patients with thyroid disease. However, some expectorants, radiographic contrast dyes, seaweed tablets, and health food supplements contain excess amounts of iodide and should be avoided because the iodide interferes with or complicates the management of antithyroid and radioactive iodine therapies.

50. Thyroid storm Is a life threatening emergency Characterized by sudden appearance of clinical signs of hyperthyroidism due to the abrupt release of T4 and T3 into circulation. Mortality is as high as 25% to 30%. Commonly associated with Grave's disease.

51. Predisposing conditions: Medical factors : • Infection • Fever • Uncontrolled toxicity • Irregular drug intake • Pregnancy, toxemia of pregnancy • Radio iodine therapy • DKA Surgical factors: Anxious and nervous patient before surgery, Too much handling of gland just before surgery. This can occur both intraoperative or in the immediate post operative period, but the latter is more common between 6-18 hours post operatively.

52. Management requires : 1. Intensive monitoring and supportive care, 2. Identification and treatment of the precipitating cause, and 3. Measures that reduce thyroid hormone synthesis.  propylthiouracil (500–1000 mg loading dose and 250 mg every 4 h) should be given orally or by nasogastric tube or per rectum. If not available, methimazole can be used in doses up to 30 mg every 12h.  One hour after the first dose of propylthiouracil , stable iodide is given to block thyroid hormone synthesis via the Wolff- Chaikoff effect (the delay allows the antithyroid drug to prevent the excess iodine from being incorporated into new hormone).  A saturated solution of potassium iodide (5 drops SSKI every 6 h) or, where available, ipodate or iopanoic acid (500 mg per 12 h) may be given orally. Sodium iodide, 0.25 g IV every 6 h, is an alternative.

53. Propranolol should also be given to reduce tachycardia and other adrenergic manifestations (60–80 mg PO every 4 h; or 2 mg IV every 4 h). High doses of propranolol decrease T4 → T3 conversion. Short-acting IV esmolol can be used to decrease heart rate.  Additional therapeutic measures include :  glucocorticoids (e.g., hydrocortisone 300 mg IV bolus, then 100 mg every 8 h),  antibiotics if infection is present,  cooling,  oxygen, and  IV fluids.

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