Hyperthyroidism  (THYROTOXICOSIS) Hyperthyroidism is only a diagnosis of excessive TH status, never means a concrete disease . It is wrong to say “Graves disease (GD)”as “hyperthyroidism ”in brief. Regardless of the pathogenesis, Hyperthyroidism is characterized by A. Thyroidal origin  1. Graves disease (GD)  2. Multiple nodular thyrotoxicosis  3. Plummer disease (toxic thyroid adenoma)  4. Hyperfunctional thyroid nodule  5. MEN with hyperthyroidism  6. Thyroid carcinomas  7. Neonatal hyperthyroidism  8. Genetic toxic thyroid hyperplasia/goiter  9. Iodine-induced hyperthyroidism B. Pituitary origin 1. Pituitary TSHoma 2. TH insensitivity syndrome 3. Para-carcinoma syndrome 4. HCG-related hyperthyroidism 5. Ovarian goiter with hyperthyroidism 6. Iatrogenic hyperthyroidism C. Transient hyperthyroidism  1. Subacute  de Quervian thyroiditis  subacute lymphocytic thyroiditis  traumatic thyroiditis  radioactive thyroiditis 2. Chronic chronic lymphocytic thyroiditis Pathogenesis Histopathology Clinical presentation Laboratory and special exams Diagnosis and differential diagnosis Treatment Graves disease  diffuse toxic goiter Basedow disease Subclinical hyperthyroidism normal TH  decreased TSH  no symptoms or signs A. Abnormalities of immune system 1. TSH-R-Ab + TSH-R →mimic TSH →hyperfunction/goiter. 2. functioning Ig →Th hypersensitivity + IL-1, IL-2 →TSH-R-Ab (TRAb) 		stimulating IgG hyperfunction(TSAb) 3. TRAb	inhibitory IgG hypofunction/antagonist 			of TSHR and	TSAb (TF1Ab, TGBAb) 		growth-stimulating IgG (TGI) Thyroid-associated ophthalmo- pathy (TAO) unknown  GAG accumulation, T cell  infiltration, edema, fibrosis and sight  loss. A. Thyroid  goiter:  symmetrical, diffuse, lobular  follicles: hyperplastic with scant colloid, papillary projections,  vascularity: increased  infiltration: lymphocytes/plasma cells  Overactivity of the thyroid gland B. Eyes  orbital contents↑, with mucoprotein,  GAG (glycosaminoglycan), and lymphocytes. C. Skin (dermopathy)  1. hyaluronic acid, chondroitin sulfates↑2. featured by separated collagen fibers, with  plaque formation,  3. lymphatic drainage decreased A. General considerations  incidence 0.5%  male: female ≈1: 4~6  common in 30~40yrs  family onset constitution C. Thyroid consistency: soft, firm, rubbery enlargement: symmetrical surface: smooth  thrill with audible bruit  D. Eyes a. non-infiltrative orbitopathy fissure widened, sclera exposed, lid retraction, lid tremor, lid lay, globe lay.  Staring gaze is one of the early signs of TAO Toxic goiter is the important feature of GD  inflammation and hypertrophy of the tissues around the eyes causing swelling b. infiltrative orbitopathy: 		excessive tearing 		exophthalmos (asymmetrical) 		eyelids unclosed 		blurred vision 		double vision 		visual acuity decreased 		corneas ulcerated and infected 		sight loss c. Classification of Graves orbitopathy: NOSPECS (American Thyroid Association) Class		Definition 0	No physical signs or symptoms 1	Only signs, no symptoms (signs limited to 		 upper lid retraction, stare, lid lag, and 		 proptosis to 22mm) 2	Soft tissue involvement (symptom and sign) 3	Proptosis>22mm 4	Extraocular muscle involvement 5	Corneal involvement 6	Sight loss (optic nerve involvement) E. Others  tremor of hands and tongue  muscle wasting  rapid reflex response  liver function  wbc↓and anemia,  vitiligo/hair loss  pretibial myxedema Early feature of pretibial myxedema: thickening of the skin over the lower legs F. Complications a. cardiopathy/heart failure 	arrhythmia, heart enlargement and failure, disappeared after treatment b. Thyrotoxic crisis 	exaggerated abruptly 	precipitating factors: infection, trauma, surgery, 	  radiation, DKA, parturition 	Additional pictures: arrhythmias, pulmonary edema,  abdominal pain, apathy, coma, shock c. hypokalemic periodic paralysis 	more common in Asia 	abruptly paralysis with hypokalemia 	precipitated by carbohydrate 		or vigorous exercise 	some companied by myasthenia gravis.  A. Serum TH and TSH  a. FT3 and FT4  b. TT3 and TT4  c. rT3  d. TSH B. TSH receptor antibodies C. TRH stimulation test 	euthyroid Graves ophthalmopathy 	GD medication D. 131I uptake and T3 suppression test E. pathological exams A. Functional diagnosis suspected when weight loss diarrhea slight fever tachycardia atrial fibrillation fatigue dysmenorrhea difficult in control of DM, TB, heart  failure, CHD, liver disease B. Types FT3 /FT4 ↑, uTSH↓:  hyperthyroidism  Only FT3 ↑, uTSH↓: T3 hyperthyroidism  Only FT4 ↑, uTSH↓: T4 hyperthyroidism  Only uTSH↓: subclinical hyperthyroidism A. General management  sedatives for restlessness/insomnia. B. Management a. medical  methylthiouracil (MTU) 			 propylthiouracil (PTU) 300~600mg/d  methimazole (MM) 	carbimazole (CMZ) 30~60mg/d 					 b. dosage and course 	1st stage (6 wks)  full dosage to control symptoms 	2nd stage (4~8wks) dosage decrease gradually 	  1/6 dosage/wk 	3rd stage (>1yr) 	  PTU 50mg/MM 5mg, Qd c. “block-replace”regimens 	TH added to prevention of 	hypothyroidism. T4 50μg, Qd.  not recommended in general d. drug withdrawal 	goiter subsides 	minimal dosage to maintain effects 	TSH return to normal 	TSAb negative 	normal response to TRH e. drug side-effects 	 agranulocytosis  (<1%, within 2 mos) 	 WBC / wk-mo C. Radioiodine (131I)  a. more commonly used than before  b. contraindications 	  pregnant 	  young people (<20yrs) 	  severe exophthalmos 	  thyrotoxic crisis 	  failed to uptake I  C. Complications hypothyroidism radiation thyroiditis 	 thyrotoxic crisis 	 exaggarated proptosis  (smokers, >40 yrs, male) D. Surgery  indications failed to medication huge thyroid tumor suspected retrosternal goiter contraindications severe proptosis 	 severe systemic diseases 	 early and late pregnancy 	 thyrotoxicosis not controlled E. Treatment decision-making a. firstly treated with medications for all patients b. after controlled, decided by 		age 		run course 		severity/complications 		thyroid states 		doctor’s experience 		patient’s willings F. Special concerns a. minimal iodide supplement b. treat severe proptosis with caution, including TH supplement and prednisone c. thyroid crisis treated with NaI, PTU, DXM, and propranolol d. PTU for pregnant cases, never makes TSH <0.5mU/L e. treated with digoxin may be dangerous in some cases  Laboratory and Special Exams Diagnosis and Differential Diagnosis C. Pathogenic diagnosis TRAb, TgAb, TPOAb, HCG, 131I uptake Treatment * Lecturer: LIAO ERYUAN Pathogenesis of Hyperthyroidism TRH TSH T3,T4 I Normal Feedback I TSHR-Ab T3,T4 Graves’Disease T3 TSH TRH GRAVES DISEASE (GD) Pathogenesis B. Other factors  genetic factors  infective factors  stress (physical or emotional) II Histopathology The thyroid follicles are lined by cuboidal  follicular epithelium Under high power microscope, the tall columnar  epithelium is lined by hyperplastic infoldings Clinical Presentation B. Hypermetabolic states nervousness (99%) irritability (90%) palpitation (88%) tachycardia (82%) insomnia (60%) fatigue (70%) heat intolerance (70%) weight loss (75%) voracious appetite (65%) menstruation changes (50%) Typical manifestations of the eyes and thyroid *