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MINISTRY OF HEALTH PROTECTION OF UKRAINE Vynnitsa national medical university named after M.I.Pyrogov «CONFIRM» on methodical meeting of endocrinology department A chief of endocrinology department, prof. Vlasenko M.V. _________________ “_31_”_august___ 2012 y METHODOLOGICAL RECOMМENDATIONS FOR INDEPENDENT WORK OF STUDENTS BY PREPARATION FOR PRACTICAL CLASSES Scientific discipline Мodule № 1 substantial module №1 Topic Course Faculty Internal medicine Basis of Internal medicine “Diagnostic, treatment and prophylactic basis of main endocrinology diseases” Topic №11: Thyrotoxicosis syndrome. Diffuse toxic goiter. Classification. Clinics. Laboratory and instrumental diagnostics. Differential diagnosis. 4 Medical № 1 Vynnitsa – 2012 METHODOLOGICAL RECOMМENDATIONS for the students of 4-th course of medical faculty for preparation to the practical classes from endocrinology 1.Тopic №11: Thyrotoxicosis syndrome. Diffuse toxic goiter. Classification. Clinics. Laboratory and instrumental diagnostics. Differential diagnosis. 2. Relevance of topic: Hyperthyroidism is the condition resulting from the effect of excessive amounts of thyroid hormones on body tissues. Thyrotoxicosis is a main syndrome. Sometimes the term hyperthyroidism can be used in a narrower sense to denote this state when the thyroid gland is producing too much thyroid hormones in contrast with excessive ingestion of thyroid hormone medication. At one time or another, approximately 0,5 % of the population suffers from hyperthyroidism. Graves disease is the most common cause of hyperthyroidism and is fairly common in the population. It is responsible for over 80 % of hyperthyroid cases. It occurs most often in young women, but it may occur in men and at any age. Thyrotoxicosis is a syndrome of clinical and biochemical displays of excessive amounts of thyroid hormones in blood, regardless of reason of increase of their level. In most cases thyrotoxicosis develops as a result of excessive thyroid hormones producting by thyroid gland (hyperthyroidism). Among all forms of thyrotoxicosis 90 % a diffuse toxic goiter and thyro-toxic adenoma make. The variety of clinical symptoms of thyrotoxicosis stipulates the origin of certain diffculties at diagnostics of disease. According to this it is especially important to be able to fnd out the symptoms of thyrotoxicosis in time, conduct differential diagnostics of its basic symptoms, estimate the features of course of disease, to appoint in time the proper treatment of diffuse toxic goiter, that helps to prevent a lot of heavy complications of the illness, such as a myocardiopathy (thyrotoxic heart), hypertension, thyrotoxic encephalopathy, rapid progress of ophtalmopathy, liver function disorders, osteoporosis. Similar clinical symptoms cause the necessity of differential diagnostics of diffuse toxic goiter with autoimmune thyroiditis, thyroid gland cancer which run across with thyrotoxicosis, so far as correct surgical treatment often keeps patient life. 3. Aim of lesson: 4. References 4.1. Main literature 1. Endocrinology. Textbook/Study Guide for the Practical Classes. Ed. By Petro M. Bodnar: Vinnytsya: Nova Knyha Publishers, 2008.-496 p. 2. Basіc & Clіnіcal Endocrіnology. Seventh edіtіon. Edіted by Francіs S. Greenspan, Davіd G. Gardner. – Mc Grew – Hіll Companіes, USA, 2004. – 976p. 3. Harrison‘s Endocrinology. Edited J.Larry Jameson. Mc Grew – Hill, USA,2006. – 563p. 4. Endocrinology. 6th edition by Mac Hadley, Jon E. Levine Benjamin Cummings.2006. – 608p. 5. Oxford Handbook of Endocrinology and Diabetes. Edited by Helen E. Turner, John A. H. Wass. Oxford, University press,2006. – 1005p. 4.2. Additional literature 6. Endocrinology (A Logical Approach for Clinicians (Second Edition)). William Jubiz.-New York: WC Graw-Hill Book, 1985. - P. 232-236. Pediatric Endocrinology. 5th edition. – 2006. – 536p. 7. Thyroid Disordes (Aclevelend Clinic Guide) by Mario Skugor, Jesse Bryant Wilder Clevelend Press,2006. – 224p. Basic Level. 1. Localization of thyroid gland. 2. Normal sizes and weight of thyroid gland. 3. Biological effects of thyroid hormones’ action. 4. Regulation of thyroid gland function. Students’ Independent Study Program. You should prepare for the practical class using the existing text books and lectures. Special attention should be paid to the following: 1. The terms “hyperthyroidism” and “thyrotoxicosis” 2. Predisposing factors of hyperthyroidism. 3. Pathogenesis of hyperthyroidism. 4. Degrees of the thyroid gland enlargement. 5. Stages of thyrotoxicosis severity. 6. Changes of the cardiovascular system in patients with hyperthyroidism. 7. Changes of the nervous system in patients with hyperthyroidism. 8. Changes of the gastrointestinal tract in patients with hyperthyroidism. 9. Changes of the other endocrine organs in patients with hyperthyroidism. 10. Ophthalmologic signs and symptoms of hyperthyroidism. 11. Endocrine encephaloophthalmopathy. 12. Pretibial mixedema. 13. Differential diagnosis of hyperthyroidism. 14. Particularities of hyperthyroidism in young, adult and pregnant patients. 15. Nodular hyperthyroidism: etiology, pathogenesis, diagnostic criteria, differential diagnosis. 16. Complications of hyperthyroidism. 17. The main methods of treatment patients with hyperthyroidism. 18. Antithyroid preparations: mechanism of action, side effects. 19. Usage of β-blockers, glucocorticoids, thyroid hormones. 20. Surgical treatment. 21. Iodine therapy. 22. Treatment of endocrine encephalopathy. 23. Thyroid storm: diagnostic criteria, treatment. Short content of the theme. The thyroid is a firm vascular organ lying in the neck, caudal to cricoid cartilage. It is composed of two nearly equal lobes connected by a thin isthmus and weights approximately 20 gr. Rests of thyroid tissue are occasionally presents in sublingual or retrosternal areas. Thyroid secrets: T3, T4,thyrocalcitonin. The thyroid hormones, thyroxine (T4) and triiodothyronine (T3) are secreted under the stimulatory influence of pituitary thyrotropin (thyroidstimulating hormone or TSH). TSH secretion is primary regulated by a dual mechanism: - thyrotropin-releasing hormone (TRH); - thyroid hormone. Thyroid hormone exits in circulation in both free and bound forma. The thyroid gland is the sole source of T4 and only 20% of T3 is secreted in the thyroid. Approximately 80% of T3 in blood is derived from peripheral tissue (mainly hepatic or renal) deiodinatoin of T4 to T3. (Thyroid hormones. Iodide, ingested in food or water, is actively concentrated by the thyroid gland, converted organic iodine by peroxidase, and incorporated (by the thyroid gland) into tyrosine in intrafollicular thyroglobulin. The thyrosines are iodinated at eihter one (monoiodotyrosine, MIT) or two (diodotyrosine,DIT) sites and then coupled to form the active hormones (diiodotyrosine + diiodotyrosine → tetraiodothyronine (thyroxine, T4); diiodotyrosine + monoiodotyrosine → triiodotyronine (T3). Thyroglobuline, a glycoprotein, containing T3 and T4 within its matrix, is taken up from the follicle as colloid droplets by the thyroid cells. Lysosomes containing proteases cleave T3 and T4 from thyroglobulin, resulting in release of free T3 and T4. The iodotyrosines (MIT and DIT) are also released from thyroglobulin but do not normally reach the bloodstream. They are deiodinated by intracellular deiodinases, and their iodine is neutralized by the thyroid gland. Although some of free T3 and T4 is deiodinated in the thyroid gland with the iodine reentering the thyroid iodine pool, most diffuses into the bloodstream where it is bound to certain serum proteins for transport. The major thyroid transport protein is thyroxine binding globulin (TBG), which normally accounts for about 80% of the bound thyroid hormones. Other thyroid binding proteins, including thyroxine-binding prealbumin (TBPA) and albumin, account for the remainder of the bound serum thyroid hormone (20 %). About 0,05 % of the total serum T4 and 0,5 % of the total serum T3 remain free but in equilibrium with the bound hormone. About 15 - 20 % of the circulating T3 is produced by the thyroid. The remainder is produced by monodeiodination of the auter ring of T4, mainly in the liver. Monodeiodination of the inner ring of T4 also occurs in hepatic and extrahepatic sites, including kidney, to yield 3,3/, 5/-T3 (reverse T3 or rT3). This compound has minimal metabolic activity but is present in normal human serum or globulin. Observations pertaining to rT3 metabolism in fetal life are of great importance. Total amniotic T4 and T3 are low, in contrast to levels in maternal serum. Fetal rT3 levels in amniotic fluid are much higher than the corresponding values in maternal serum throughout pregnancy (15 to 42 wk). These data imply that rT3 derives primarily from the fetus and that it may be possible to diagnose fetal hypothyroidism as early as 15 wk of pregnancy, utilizing radioimmunoassay for rT3. These levels appear to decrease after 30 wk gestation and may be serve as a useful index of pregnancies of < 30 wk duration. Physiologic effects of thyroid hormones Thyroid hormones have a major physiologic effects: 1) they increase protein synthesis in virtually every body tissue 2) they increase O2 consumption by increasing the activity of Na+ H+ ATPase (Na pump), primarily in tissues responsible for basal O2 consumption (i.e., liver, kidney, heart and skeletal muscle).) Hyperthyroidism (thyrotoxicosis) Toxic diffuse goiter. Grave’s diseaseis the condition resulting from the effect of excessive amounts of thyroid hormones on body tissues. Etiology: Autoimmune disorders, which can be provoked by: - insolation; - acute infections; - hormone disbalance (pregnancy and others). Pathogenesis. Insufficiency of T suppressors excessive level of T helpers increasing function of B lymphocyte secretion of thyroid – stimulating immunoglobulin (TSI) blood the thyroid. TSI works as an antibody to the thyrotropin receptor on the thyroid follicular all resulting in stimulation of this receptor secretion of T4, T3. Clinical manifestations The clinical presentation may be dramatic or subtle. Cardiovascular system Dysfunction of the cardiovascular system is common, and in some instances, the only manifestation of hyperthyroidism. Heart rate and cardiac output are increased, and peripheral resistance is decreased. These changes result in: - constant palpitation; -sinus tachycardia or atrial fibrillation; -heart failure. Examination reveals: - tachycardia; - widened pulse pressure; - a prominent apical impulse; - bounding arterial pulsation; - accentuated heart sounds; - systolic ejection murmurs; - occasionally cardiac enlargement.. Other than arrhythmia, electrocardiographic changes are limited to nonspecific ST and T wave abnormalities. Psychological symptoms: - nervousness; - physical hyperactivity; - emotional lability; - anxiety; - distractibility; - insomnia. These changes occur commonly and often result in impairment of work or school performance and disturbances in home and family life. Neuromuscular symptoms: - a fine tremor is often evident in the hands and fingers; - performance of skills requiring fine coordination becomes difficult; - deep tendon reflexes are hyperactive; - some evidence of myopathy is common; - weakness lit usually develops gradually, is progressive, and may be accompanied by muscle wasting. Skin. The skin is warm, fine, moist and its texture is smooth or velvety erythema and pruritus may be present. Increased sweating is common complaint . Hair may become thin and fine, and alopecia occurs. Infiltrative dermopathy, also known as pretibial mixedema (a confusing term, since mixedeme suggests hypothyroidism), is characterized by nonpitting infiltration of proteinaceous ground substance, usually in the pretibial area. The lesion is very pruritic and erythematous in its early stages and subsequently becomes browny it may appear years before or after the hyperthyroidism. TSIS are invariably present. The dermopathy usually remits spontaneously after months or years. Eyes. Eye sings include: - stare (Schtelvag’s symptom); - lid lag; - lid retraction (symptoms of Dalrympl; Greffe; Koher), which results in “apparent” proptosis, but not eye and is often accompanied by symptoms of: - conjunctival irritation. These eye signs are largely due to excessive adrenergic stimulation and zemit promptly after upon successful treatment of thyrotoxicosis - infiltrative ophthalmopathy is present in 20 to 40% of patients with Graves’ disease. It is characterized by increased retro-orbital tissue, producing exophthalmos and by lymphocyte infiltration of the extraocular muscles, producing a spectrum of ocular muscle weakness frequently leading to blurred and double vision. The pathogenesis of infiltrative ophthalmopatny is poorly understood. It may occur before the onset of hyperthyroidism or as 15 to 20 years afterward and frequently worseness or improves independent of the clinical course of hyperthyroidism. Infiltrative ophthalmopathy results from immunoglobulins directed to the extraocular muscles and specific antibodies that cause retro – orbital inflammation and subsequent edema (it is not because of TSH or LATS). The antibodies are distinct from those initiating Graves’ type hyperthyroidism. The symptoms include: - pain in the eyes; - lacrimation; - photophobia; - diplopia; - blurring or loss of vision. The major signs are: - proptosis (exophthalmos); - periorbital and conjunctival congestion and edema (chemosis); - limitation of ocular mobility. Thyroid gland Enlargement of thyroid gland is very common. Both thyroid lobes are usually moderately symmetrically enlarged, but thyroid enlargement may be absent. Degrees of thyroid gland enlargement. 0- we can’t see or palpate thyroid gland; IA- we can’t palpate but can’t see; IB- thyroid gland can be seen when patient put head back; II –thyroid gland can be seen in normal position of the head. III – thyroid gland can be seen from the distance of 5 meters or more Respiratory function Abnormalities of respiration include: - decreased vital capacity; - decreased pulmonary compliance. They result in dyspnea and hyperventilation during exercise and sometimes rest. Gastrointestinal system Increased caloric utilization is almost always present. It results in increased appetite and food intake, but compensation is usually inadequate, and modest loss occurs. Increased gastrointestinal motility may result in increased frequency of bowel movements and even frank diarrhea. Minor abnormalities in hepatic function are often found. Hematopoetic system Some patients have a modest anemia, caused by mild deficiency in one or more hematopoetic nutrients or increased plasma volume. Mild granulocytopenia and thrombocytopenia may be present. Energy and intermediary metabolism because of increased energy expenditure, energy production must be augmented, this is accompanied by increased oxygen consumption and heat production. In patients with diabetes mellitus, requirement for exogenous insulin catabolism. Endocrine system In women, hypomenorrhea or amenorrhea may occur, although no changes are noted. In men, there may be loss of libido and impotence hypercalcemia is found occasionally; it is caused by increased bone resorption, but clinical osteopenia is rare. In patients mild adrenal insufficiency may occur. It is present by low diastolic blood pressure and darkness of upper lid (Elynecks symptom). Degrees of severity of thyrotoxicosis I. mild degree: work capacity is normal; heart beat – is under 100/min; weight loss is less than 10 %. II. moderate degree: work capacity is decreased; heart beat – is 100 to 120/min; weight loss is 10 to 20 %. III. severe degree: patients cant work; heart beat – is over 120/min and arrhythmia is present; weight loss is more than 20%. Criteria Clinical signs Mild Moderately expressed Neurological symtoms Expressed insignifcantly Decline of working capacity Insignifcant Decline of body mass To 10 % of initial Moderate More expressed Severe Considerably expressed Considerable changes, Considerable emotional and muscular weakness, vegetative violations, muscular atrophy of proxymal weakness, atrophy of proxymal muscle departments of muscle departments of extrem- extremities, hypotho-nia ities, hypothonia of skeletal of skeletal muscles are muscles more expressed Considerable Complete loss of capacity To 20 % of initial More than 20 % of initial More than 120 min, arrhythmia Pulse To 100 min To 120 min Pulse pressure Rises insigni-fcantly Rises considerably Rises considerably Signs of insuffciency of blood circulation Absent Insuffciency of blood circulation of 1 degree Insuffciency of blood circulation of 2–3 degrees Ophtalmopathy Thyreotoxic ophtalmopathy Endocrine ophtalmo-pathy of 1 degree Endocrine ophtalmopathy of 2–3 degrees Levels of T3, T4 in Increased to 15 % of the high normal blood level Increased to 60 % of the high normal level Increased more than on 60 % of the high normal level Diagnosis of toxic diffuse goiter I. Clinical manifestations (were discussed). II. Laboratory findings. (The diagnosis of hyperthyroidism is usually straightforward and depends on careful clinical history and physical examination, a high index of suspection, and routine thyroid hormone determination). 1. In most patients serum total T3 and T4 concentrations, are increased (however, these changes, also can be caused by increased thyroxine – binding globulin production, e.g. as a result of estrogen therapy). 2. Elevation of T3 - resin uptake. (T3 - resin uptake is not a measurement of circulating T3. In normal patients, 25 to 35% of TBG binding sites are occupied by thyroid hormone. When 131I-T3 is added to the patients serum, in vitro, a portion binds to unoccupied TBG sites. After equilibration, a resin is added that binds the remaining unbound 125/-T3). Thus in hyperthyroidism, characterized by increased levels of circulating thyroid hormone, there are more occupied and less unoccupied TBG binding sites. Less 131I-T3 is bound to TBG, resulting in more uptake of 131I-T3 by the resin. 3. TSN (serum thyroid stimulating hormone) may be decreased, but it is not very sensitive assay in the assessment of thyroid hyperfunction. 4. If the diagnosis of hyperthyroidism remains unclear after these initial tests, more expensive, sophisticated and time – consuming tests may be required, e.g. A TRH test (thyrotropin releasing hormone). Serum TSN is determined before and after an i/v injection of 500 mkg of synthetic TRH. Normally, there is a rapid rise in TSH of 5 to25 mkU/ml, reaching a peak in 30 min and returning to normal by 120 min. In patients with hyperthyroidism TSH release remains suppressed, even in response to injected TRH, because of the inhibitory effects of the elevated free T4 and T3 on the pituitary thyrotroph cells. The diagnosis of infiltrative ophthalmopathy when hyperthyroidism is or recently was present is not difficult. The diagnosis is less certain if the patient is not or never was hyperthyroid orbital ultrasonography or computed tomography is the best procedure to confirm the diagnosis of ophtalmopathy such as orbital pseudotumor and orbital tumors. Differential diagnostics of diffuse toxic goiter (Graves’ disease) and functional autonomy of thyroid gland Sign Diffuse toxic goiter Functional autonomy Character of illness Autoimmune disease Iodine-defcit disease Palpation of thyro- More frequent diffuse en- More frequent multinodular id gland largement of thyroid gland; goiter in a 10 % goiter absent Age of patient Anamnesis Young age (20 – 40 years) Short More senior 45 – 50 years Protracted motion of euthyroid goiter Clinic of thyrotox-icosis More frequent manifesting Ophtalmopathy Clinically obvious endocrine ophtalmopathy in 50 % cases Often olygosymptomic or monosymptomic course There is not endocrine ophtal-mopathy (not to mix up thyrot-oxicosis with eye symptoms!) Pretibial It is in 3–4 % patients myxed-ema Antibodies to In most cases, appear (most specifc the thyroid antibodies –rTSH) gland Contents of Maintenance in blood of T4 and T3 thyroid is increased hormones in blood Radioisotope The diffuse strengthening of scanning of fascination of Tc-99m at scintigraphy thyroid gland Ultrasonography Diffuse enlargement of the thyroid gland Proof remision after the protracted Treatment thyreostatic therapy in the group of patients correctly selected for this treatment in 30 – 40 % cases Tests and Assignments for Self-assessment. Multiple Choice. Choose the correct answer/statement: 1. The normal weight (gr.) of the thyroid gland is: Absent Usually absent Maintenance in blood mainly T3 (T3thyrotoxicosis), rarer T4 is increased Hot nodules or alternation of areas of increased and decreased accumulation of Tc-99m A nodule is determined Thyreostatic therapy liquidates thyrotoxicosis only on the time of getting preparations and generally have no perspectives A. 7 – 10; B. 1 – 3; C. 20 – 30; D. 45 – 55; E. 50 – 60. 2. Clinical sign of hyperthyroidism which is very rare in old patients: A. large goiter; B. parkinsonic’ trembling of the fingers; C. nodular forms of goiter; D. prominent heart failure; E. atrial fibrillation. 3. In a woman of 50 years old atrial fbrillation is found out. In anamnesis there are colds, acute tonsillitis. Objectively: temperature of 37,1 °C, heart rate – 128/min., pulse – 128/min., blood pressure is 145/60 mmHg. The thyroid gland enlargement of 3 grade. Left border of heart on 2 cm outside from a left media-clavicular line. Tones of heart are intensives, systolic murmur above an apex, accent of II sound in second rib on the left near a breastbone. A skin is moist. Manifestation of what disease may be arrhythmia most probably? A. Diffuse toxic goiter B. Climacteric cardiomyopathy C. Rheumatic vice D. Dilatational cardiomyopathy E. Miocardiatic cardiosclerosis 4. A woman of 47 years old complains of weakness, hyperhid-rosis, shaking in a body, loss of weight, palpitation, increasing the sizes of neck, lacrimation, photophobia. Objectively: a thyroid gland is diffusely enlarged, elastic, mobile, painless. Heart rate - 128/min, atrial fbrillation. What symptom in all will allow to estimate the degree of thyrotoxicosis severity more reliable? A. Presence of arrhythmia B. Size of thyroid gland C. State of eyeballs D. Hight and weight E. Numbers of arterial pressure 5. A woman of 25 years old has a diffuse toxic goiter during 5 years. Emotionally instable, at examination there is tremor of fngers of hands, skin moist, heat feeling, an apex shove is increased, the heart bounds are displaced to the left, atrial fbrillation, systolic murmur on an apex. Pulse 96/min, blood pressure is 170/70 mmHg. A thyroid gland is enlarged to the 3 grade. What pathogenetic mechanisms lies in basis of violation of cardio-vascular system function of patient? A. Damage action of thyroid hormones on the myocardium B. Increasing sensitiveness of receptors to katecholamines C. Increasing of albuminous substrats catabolism D. Infuencing of thyreostimulated antibodies E. Change of vegetative nervous system tone 6. The patient of 32 years complains of permanent irritability, palpitation, pain in eyes, lacrimation, tremor of extremities and all body, hy-perhydrosis, weight loss of 10 kg for 4 months. Objectively: skin is warm, moist, mild exophthalmos, there are symptoms of Grefe, Kokher, Mebius. A thyroid gland is diffusely enlarged, that is seen at swallowing, painless. Pulse - 108/min, blood pressure is 140/66 mmHg. Shallow tremor of fngers of hands. Your diagnosis? A. Diffuse toxic goiter B. Fibrous thyroiditis C. Diffuse nontoxic goiter D. Nervous exhaustion E. Subacute thyroiditis Answer: 1 – B. 2 – A. 3 – A. 4 – A. 5 – A. 6 – A. Real-life situations to be solved: Patient F, 38 years old, complaints on general weakness, increased sweating, palpitation. Physical examination shows: skin is moist, hot; trembling of the fingers, thyroid gland is enlarged, positive eye’s symptoms, pulse rate 116/minute, systolic murmur on the region of the heart and thyroid. Put previous diagnosis and make the plan of the examination. Answer: Hyperthyroidism, moderate stage of thyrotoxicosis. Ultrasonic examination of the thyroid gland, the levels of TSH, T3,T4. Students Practical Activities. Work 1 : Students’ group is divided into 2 sub-groups, that work near the patients’ bed: ask the patients on organs and systems, take anamnesis of the disease , anamnesis of life, make objective exam. With the teacher’s presence. In the class-room they discuss the patients, learn data of laboratory and instrumental exam. of these patients. 1.To group the symptoms into the syndromes. 2.To find out the leading syndrome and make differential diagnosis. 3.To formulate the diagnosis. 4.To make a plan of treatment. Methodological recommendation prepared assistant, c.m.s. Chernobrova O.I. It is discussed and confirm on endocrinology department meeting " 31 " august 2012 y. Protocol № 1.