Hyperthyroidism mainly from Harrison.pptx

Hyperthyroidism mainly from Harrisons 21 st edition

1. Hyperthyroidism Dr Varesh NagraTH ,9838071306 Reference: Harrison's

2. THYROTOXICOSIS Thyrotoxicosis :Excess H yperthyroidism : Excess due to over production

3. THYROTOXICOSIS Table 335-6 Causes of Thyrotoxicosis Primary hyperthyroidism    Graves' disease   Toxic multinodular goiter   Toxic adenoma   Functioning thyroid carcinoma metastases   Activating mutation of the TSH receptor   Activating mutation of G sa (McCune-Albright syndrome)    Struma ovarii   Drugs: iodine excess ( Jod-Basedow phenomenon) Thyrotoxicosis without hyperthyroidism    Subacute thyroiditis   Silent thyroiditis   Other causes of thyroid destruction: amiodarone , radiation , infarction of adenoma   Ingestion of excess thyroid hormone (thyrotoxicosis factitia ) or thyroid tissue Secondary hyperthyroidism   TSH-secreting pituitary adenoma   Thyroid hormone resistance syndrome: occasional patients may have features of thyrotoxicosis   Chorionic gonadotropin-secreting tumors a    Gestational thyrotoxicosis a

4. Predisposing factors of Graves' Predisposing factors As in autoimmune hypothyroidism, a combination of environmental and genetic factors . Genetics :Concordance in monozygotic twins is 20-30%, compared to <5% in dizygotic twins. Smoking is a minor risk factor for Graves' disease and a major risk factor for the development of ophthalmopathy. Stress Sudden increases in iodine intake may precipitate Graves' disease. Post partum :3x

5. PATHOGENESIS TSH RECEPTOR Ab ( TRAb ) For confirmation of Graves (Sens 95%) Useful in pregnancy +graves –it crosses placenta- neonatal thyrotoxicosis Can predict remission

6. PATHOLOGY of opthalmopathy EOM SWELLING : Infiltrated by activated T cells , release cytokines :I FN-Gama , TNF, and IL-1 F ibroblast activation > glycosaminoglycans produced > trap water EOM Fibrosis Later , irreversibl e I ncreased fat is an additional cause of retrobulbar tissue expansion. The increase in intraorbital pressure can lead to proptosis , diplopia , and optic neuropathy

7. INCIDENCE Graves ' disease accounts for 60-80% of thyrotoxicosis. The prevalence varies among populations, depending mainly on iodine intake (high iodine intake is associated with an increased prevalence of Graves' disease) Graves' disease occurs in up to 2% of women but is one-tenth as frequent in men . The disorder rarely begins before adolescence and typically occurs between 20 and 50 years of age , but it also occurs in the elderly.

8. C/F : Excludes the signs of ophthalmopathy and dermopathy specific for Graves' disease. Table 335-7 Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency) Signs and Symptoms of Thyrotoxicosis (Descending Order of Frequency) Symptoms Signs   Hyperactivity, irritability, dysphoria   Heat intolerance and sweating   Palpitations   Fatigue and weakness    Weight loss with increased appetite (5% Wt gain)   Diarrhea   Polyuria   Oligomenorrhea, Amenorrhoea loss of libido   Tachycardia; atrial fibrillation in the elderly    Tremor    Goiter    Warm, moist skin   Muscle weakness, proximal myopathy ,hyperreflexia,wasting    Lid retraction or lag   Gynecomastia Chorea Rare

9. C/F:CVS Pulse Rate :High Rhythm :AF in > 50 yr . Tr of Thyrotoxicosis converts to SR in 50%) Volume :Bounding , boad PP Auscultation : Aortic systolic murmur Worsening of angina or heart failure (IN elderly or preexisting heart disea se

10. C/F contd Palmar erythema , onycholysis , and, less commonly, pruritus , urticaria , and diffuse hyperpigmentation may be evident. Hair texture may become fine, D iffuse alopecia :40% , takes months to improve Osteopenia , # M ild hypercalcemia :In 20% H ypercalciuria

11. O/E Gland :Diffuse enlargement 2-3X T hrill or bruit m/b+

12. O/E :Graves opthalmopathy Lid retraction , staring appearance (Any thyrotoxicosis,due to sympathetic overactivity ) Graves' ophthalmopathy . Syn: Th yroid-associated ophthalmopathy , Causes :10% inA utoimmune hypothyroidism or thyroid antibodies . Time line Starts 1 year +/- of onset of Graves disease Sometime several year +/- , m/b euthyroid ophthalmopathy.

13. Graves’ OPTHALMOPATHY Symptoms : m/b Unilateral in 10% Grittiness , eye discomfort , and excess tearing Diplopia in 5-10% if muscle swelling is severe . On Up&lateral gaze Sign : Lid lag Proptosis –on Exopthalmometer Corneal exposure Periorbital edema ,scleral injection , Cheimosis Investigation : CT/USG orbit :E nlarged extraocular muscles in all pts Complication : Co mpression of the optic nerve at the apex of the orbit - papilledema , peripheral field defects , and, if left untreated, permanent loss of vision .

14. Graves’ OPTHALMOPATHY Orbital changes in Graves' disease "NO SPECS” scheme 0 = N o signs or symptoms 1 = O nly signs (lid retraction or lag), no symptoms 2 = S oft tissue involvement (periorbital edema) 3 = P roptosis (>22 mm) 4 = E xtraocular muscle involvement (diplopia) 5 = C orneal involvement 6 = S ight loss patients do not necessarily progress from one class to another referral to an ophthalmologist is indicated

15. Graves’ OPTHALMOPATHY Lid retraction Periorbital edema Conjunctival injection Proptosis

16. Graves’ DERMOPATHY Thyroid dermopathy : In <5% , almost asso with Mod-severe opthalmopatthy Site :Pretibial , anterior and lateral leg Myxoedema :Thickening of skin N oninflamed , indurated plaque D eep pink or purple color and an "orange-skin" appearance. Nodular involvement can occur, Rarely whole leg and foot involvement D/D E lephantiasis .

17. B. Thyroid dermopathy over the lateral aspects of the shins.

18. Graves' Disease Thyroid acropachy :Thickening of acral parts, <1% Triad of : D igital clubbing Soft tissue swelling of the hands and feet Periosteal new bone formation. Asso : Th yroid dermopathy

19. C. Thyroid acropachy.

20. GRAVES IN ELDERLY Only fatigue / wt loss :Apathetic graves (D/D Depression) AF

21. LABORATORY EVALUATION

22. Investigation in Graves' Disease Low TSH/High FT4/High FT3 Low TSH, Normal FT4, FT3 elevated :In 2-5% , T3 toxicosis Low TSH , Elevated total T4,Elevated FT4 ,Normal T3 k/a T4 toxicosis Seen in areas with excess iodine , providing surplus substrate for thyroid hormone synthesis. Measurement of TPO antibodies is useful in differential diagnosis . Measurement of TBII or TSI will confirm the diagnosis but is not needed routinely. Asso : B ilirubin , liver enzymes, and ferritin. Microcytic anemia and thrombocytopenia may occur.

23. Graves' Disease D/D Diagnosis of Graves' disease is straightforward in a patient with: Biochemically confirmed thyrotoxicosis, Diffuse goiter on palpation, Ophthalmopathy, Positive TPO or TSH-R antibodies, Often a personal or family history of autoimmune disorders.

24. Graves' Disease In doubtful patients do a radionuclide scan Graves :D iffuse, high uptake MNG Toxic adenoma Thyroiditis Ectopic thyroid tissue Factitious thyrotoxicosis.

25. Thyrotoxicosis with decreased RaI uptake Thyroiditis (Thyroglobulin is elevated) Thyrotoxicosis factita (Thyroglobulin is decreased) Iodine excess Ectopic thyroid tissue, particularly teratomas of the ovary (struma ovarii ) (Rare) Functional metastatic follicular carcinoma (Rare)

26. Graves' Disease D/D Non supressed TSH + High free T4 TSH-secreting pituitary tumor : D iffuse goiter. CT/MRI pituitary fossa Panic atta cks M ania P heochromocytoma W eight loss associated with malignanc y .

27. Graves' Disease COURSE Some pts spontaneous relapses and remissions . Rarely, fluctuation between hypo- and hyperthyroidism due to changes in the functional activity of TSH-R antibodies. 15% of patients who enter remission after treatment with antithyroid drugs develop hypothyroidism 10-15 years later as a result of the destructive autoimmune process.

28. COURSE … Ophthalmopathy W orsens over the initial 3-6 months , followed by P lateau for next 12-18 months , A pontaneous improvement , particularly in the soft tissue changes. Fulminant course in 5% :Optic nerve compression or corneal ulceration . Diplopia :Late due to fibrosis of the extraocular muscles . Rai treatment worsens eye disease in a small proportion of patients (especially smokers). Antithyroid drugs or surgery have no adverse effects on the clinical course of ophthalmopathy . Thyroid dermopathy , when it occurs, usually appears 1-2 years after the development of Graves' hyperthyroidism; it may improve spontaneously.

29. Graves' Disease GRAVES' DISEASE: TREATMENT reducing thyroid hormone synthesis: Antithyroid drugs Radioiodine ( 131 I) treatment Thyroidectomy

30. Tr –Antithyroid drugs T hionamides , such as propylthiouracil, carbimazole, and the active metabolite of the latter, methimazole. All inhibit the function of Thyroid peroxidase (which helps in o xidation and organification of iodide. ) Propylthiouracil inhibits deiodination of T 4 to T 3 These drugs also reduce thyroid antibody levels Half life PTU : 90 minute Carbimazole : Slightly less than 6 hr Methimazole 6 hr .

31. Tr … Start with carbimazole or methimazole : Carbimazole/Methimazole : 10-20 mg every 8 or 12 h PTU : 100-200 mg 6-8 hour Maintain after euthyroidism achieved :OD Block-replace regimen: High doses +L evothyroxine to avoid drug-induced hypothyroidism.

32. PTU Indications First trimester of pregnancy, the Thyroid storm Carbimazole/ Metimazole :S/E OD Dose is not possible even after euthyroidism achievement S/E Hepatotoxicity Watch LFT

33. TR.. REVIEW :3-4 week Dose titrated on basis of :FT4 TSH :Remains suppressed for Several mo . Maintenance dose :Usually 5-10 mg of carbimazole or methimazole and 50-100 mg of PTU Remission achieved :By 18-24 month in 40% pts In Block & replace regimen :Remission achieved in 6 mo After remission is achieved closely follow for 1 yr & then annually

34. S/E of drugs : R ash , urticaria , fever , and arthralgia (1-5% of patients). Either resolve spontaneously or May need substituting an alternative antithyroid drug. Tr : Antihistaminc Rare but Major (Never restart ) H epatitis :PTU (Avoid in children) Vasculitis A granulocytosis (<1%) : Sore throat,Fever , Oral ulcer Idiosyncratic & abrupt-serial testing for detection not useful

35. Graves' Disease TR … Propranolol (or Atenolol) 20-40 mg every 6 h Helpful in initial stages of treatment Thyrotoxic periodic paralysis AF :Anticoagulation In thyrotoxic state :Lesser dose of Coumarin& higher of Digoxin

36. TR Radioiodine Indications : Drug Naïve or in relapse C/E : Pregnancy & Lactation. Can conceive after 6 mo Opthalmopathy :Worsens , esp in smokers Preparation :Stop iodine containing drugs Carbimazole/Methimazole Stop 2-3 days prior ,o/w I uptake dec PTU :Stop several weeks before or higher dose of RaI Dose :Let specialist decide. Strategy c/b Ablate & replace –advantage-single dose S/E : Radiation thyroiditis : 1-2 week after treatment Thyrotoxic crisis : Prevention : Pre tr with antithyroid x1 mo prevents ,by depleting thyroid hormone Elderly Cardiac pt Relapse : Second dose after 6 mo Hypothyroidism : 10-20% in first year ,then 5%/year ,Most pts 5-10 yr later After RAI :Restart oral after 3-7 days, Give for 2-3 mo +Propranolol

37. Radioiodine tr S/E : Radiation thyroiditis : 1-2 week after treatment Thyrotoxic crisis : Prevention : Pre tr with antithyroid x1 mo prevents ,by depleting thyroid hormone Elderly Cardiac pt Relapse : Second dose after 6 mo Hypothyroidism : 10-20% in first year ,then 5%/year ,Most pts 5-10 yr later Risk of cancer : minimal After RAI :Restart oral after 3-7 days, Give for 2-3 mo + Propranolo . Avoid contact with pregnant & children for 7 days

38. TR SUBTOTAL or near total thyroidectomy Indications : Patient preference in relapse pts ; large goiter Prerequisite : Control toxicosis by oral drugs Potassium Iodide 1-2 drops tds for 10 days to prevent thyroid storm Complications : Recurrent laryngeal nerve damage Hypoparathyroidism Laryngeal edema Recurrence :<2% Hypothyroidism later

39. Graves' Disease IN PREGNANCY 14-16 week :PTU-Doesn’t cross placenta - watch LFT- Thereafter :Carbimazole/Methimazole.( (Third trimester m/b drug free) Carbimazole dose :1/10 th of PTU Target :FT4/TotalT4 at or just above the preg ref range S/E to fetus : Hypothyroidism& Goiter : More if higher dose of Carb/Meth to mother .Therefore use lower dose /titration regimen (Not blocking doses) Carbi / Methi : Esp if first trimester , aplasia cutis,c hoanal atresia and TE fistula Fetal thyrotoxicosis/Neonatal too : If Thyroid stimulating immunoglobulins are 3x after 26 week Suspect : IUGR,fetal HR > 160 ,fetal goiter ,advance bone age Tr :Antithyroid Rx to mother . Neonate may need drugs for 1-3 mo

40. PREGNANCY CONTD Stop oral drugs at presentation if Euthyroid on <7.5-15 mg carbimazole <100-200 mg PTU Small goiter Continue oral drugs at presntation if Taking higher dose Large goiter After delivery : Watrch for relapse in post partum Breast-feeding is safe with low doses of antithyroid drugs.

41. THYROID STORM / THYROTOXIC CRISIS Rare PPT causes : Ac illness :Stroke, infection, trauma, diabetic ketoacidosis Surgery (especially on the thyroid) Radioiodine treatment of partially treated or untreated hyperthyroidism. C/F High F ever +Altered sensorium - delirium , seizures , coma V omiting , diarrhea , and jaundice . High output heart failure , AF Prognosis :Mortality 30% , even with treatment.

42. THYROID STORM / THYROTOXIC CRISIS In ICU Treat the ppt cause PTU : 600 mg loading dose and 200-300 mg every 6 h . Orally/RT/Per rectum One hour after PTU :Iodine to block thyroid hormone synthesis via the Wolff- Chaikoff effect . Saturated Potassium Iodine : 5 drops SSKI every 6 h I podate or iopanoic acid (0.5 mg every 12 h), may be given orally. PTU pre-tr prevents incorporation of iodine for new hormone synthesis Propranolol : 40-60 mg orally every 4 h (High doses decrease T4 to T3 conversion) D examethasone, 2 mg every 6 h or Hydrocortisone 300 mg stat,then 100 mg tds A ntibiotics if infection is present, C ooling , oxygen , and intravenous fluids . Cholestyramine to sequester thyroid hormones

43. OPTHALMOPATHY TR Mild-Mod :No tr ,spontaneous improvement ,stop smoking Discomfort :A rtificial tears (e.g., 1% methylcellulose), paraffin based eye ointment, and the use of dark glasses with side frames. Periorbital edema may respond to a more upright sleeping position or a diuretic . Corneal exposure during sleep can be avoided by using patches or taping the eyelids shut. Minor degrees of diplopia improve with prisms fitted to spectacles. Some authorities also advocate selenium 100 μg bid. Severe ophthalmopathy, with optic nerve involvement or chemosis resulting in corneal damage, is an emergency . Short-term benefit can be gained in about two-thirds of patients by the use of high-dose glucocorticoids (e.g., prednisone, 40-80 mg daily), sometimes combined with cyclosporine .

44. Graves' Disease Pulse therapy with IV methylprednisolone: 500 mg /week for 6 week then 250 mg once weekly for 6 weeks When glucocorticoids are ineffective, orbital decompression Proptosis recedes an average of 5 mm , but there may be residual or even worsened diplopia. External beam radiotherapy m/b used .Steroids are better Teprotumumab: FDA gave breakthrough designation . Rapidly improves proptosis,diplopia , clinical activity score, and quality of life. Thyroid dermopathy does not usually require treatment but can cause cosmetic problems or interfere with the fit of shoes. Surgical removal is not indicated. If necessary, treatment consists of topical , high-potency glucocorticoid ointment under an occlusive dressing. Octreotide may be beneficial in some cases.

45. Other Causes of Thyrotoxicosis Destructive thyroiditis typically presents with a short thyrotoxic phase due to the release of preformed thyroid hormones and catabolism of Tg . True hyperthyroidism is absent, as demonstrated by a low radionuclide uptake. Circulating Tg levels are usually increased . Other causes of thyrotoxicosis with low or absent thyroid radionuclide uptake include thyrotoxicosis factitia ; iodine excess and, rarely, ectopic thyroid tissue , particularly teratomas of the ovary ( struma ovarii ) ; and functional metastatic follicular carcinoma. Whole-body radionuclide studies can demonstrate ectopic thyroid tissue . Thyrotoxicosis factitia can be distinguished from destructive thyroiditis by the clinical features and low levels of Tg .

46. Other Causes of Thyrotoxicosis TSH-secreting pituitary adenoma is a rare cause of thyrotoxicosis. It can be identified by the presence of an inappropriately normal or increased TSH level in a patient with hyperthyroidism , diffuse goiter , and elevated T 4 and T 3 levels . levated levels of the alpha subunit of TSH , released by the TSH-secreting adenoma, support this diagnosis, which can be confirmed by demonstrating the pituitary tumor on MRI or CT scan .