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Uniwersytet Mikołaja Kopernika w Toruniu Collegium Medicum im. L. Rydygiera w Bydgoszczy Emergencies Roman Junik Katedra i Klinika Endokrynologii i Diabetologii z Pracownią Medycyny Nuklearnej Endocrinological emergencies Thyroid storm (thyroid crisis, crisis thyreotoxica) Thyroid storm: a life threatening exacerbation of the hyperthyroid state characterized by decompensation of one or more organ systems. True thyroid storm is a rare event, while less severe forms are not exceptional and may be a medical emergency requiring prompt recognition and adequate treatment. Patients in whom preexisting hyperthyroidism has not been diagnosed or has been treated insufficiently. Diagnosis is mostly based on clinical findings Laboratory thyroid function tests can not differentiate thyrotoxicosis and thyroid storm. Factors that may precipitate: infectious diseases, ketoacidosis, 131-I treatment, thyroidal surgery, vigorous palpation of the thyroid gland, acute trauma, toxemia of pregnancy, parturition, administration of iodinecontaining materials (amiodarone, iodinated contrast dyes), withdrawal of antithyroid drugs, acute heart failure, pulmonary embolism, stroke and insulin-induced hypoglycemia. Sometimes no precipitating event is detectable. Manifestations: Severe hypermetabolism with high fever which changes to hyperpyrexia, profuse sweating, tachyarrythmias, high-out-put heart failure, diarrhea and vomiting. Irritability and restlessness can cause severe agitation, confusion, seizures, delirium, and coma. Dehydratation with electrolytes imbalance is another frequent feature . Patients can have a wide range of signs and symptoms. Younger patients often present sympathetic related symptoms, while older one frequently show cardiovascular dysfunctions . Thyroid storm requires aggressive reversal of thyronines toxic effect with antithyroid drugs, management of signs and symptoms and treatment of the underlying precipitating event. Antithyroid agents are propylthiouracil (PTU) and methimazole (MMI). These agents inhibit synthesis of new thyroid hormones interfering with iodide oxidation and organification. PTU also inhibits peripheral conversion of T4 to T3. MMI is available in parentheral form (Favistan, Asta Germany, amp. 40 mg). This form is unknown in USA. The recommended dose for MMI is 80-120 mg intravenously or 60-100 mg orally, via nasogastric tube or through rectal administration in divided doses. The dose for PTU are 200-250 mg every six hours. The effect of antithyroid drugs is delayed. The agent which rapidly inhibit the release of thyroid hormones is iodine. Iodine containing compounds are Lugol’s solution (60-80 drops daily), potassium or sodium iodide (2-10 drops every 8 hours) given intravenously. Lithium carbonate 250 mg every 6-8 hours can be an alternative of iodine. Betaadrenergic (β) blockers are used to decrease sympathomimetic symptoms and block the adrenergic sites, which are thought to be stimulated by hyperactive catecholamines released by the thyroid hormones. These drugs control autonomic effects of thyroid hormones and block peripheral conversion of T4 to T3. Propranolol 40-80-120 mg every 6 hours p.o. or 1-3 mg i.v. Glucocorticoids also inhibit peripheral conversion of T4 to T3. They are beneficial in sustaining the peripheral circulation and preventing shock = correction of the relative adrenal insufficiency. Hydrocortisone 300 mg iv and then 100 mg every 6-8 hours or dexamethasone 2 mg iv every 6 hours significantly reduce mortality rates. Hyperthermia should be controlled with acetaminophen, chlorpromazine, meperidine, cooling blankets or ice packs. Supportive measures such as oxygen and intravenous fluids should be given in case of hypoxia or dehydration. Removal of excess thyroid hormones from the circulation by plasmapheresis or peritoneal dialysis - in extreme situations. All medicaments should be used in maximal doses. Myx(o)edema coma It can be the first presentation of new hypothyroidism, typically in elderly woman who presents during the winter, often precipitated by infection, stroke, myocardial infarction, congestive heart failure, respiratory disease, drugs (sedative, lithium and amiodarone) or exposure to cold or discontinuing thyroxine treatment. About one third of patients have infections, but fever and tachycardia will be absent. Physical findings: puffed myxoedematous face, macroglosia, periorbital edema, and coarse, sparse hair. Hypoventilation and bradycardia. Non-pitting edema of the lower extremities. The goitre may be or not. The postoperative scar on the neck remaining after thyroidectomy may suggest postoperative hypothyroidism and may lead to the right diagnosis. Tendon reflexes are prolonged and that there are changes in the patient's consciousness. In the auxiliary investigation concentration of FT4 decreased, whereas TSH concentration was high or merely slightly increased, which could be caused by other simultaneous illnesses. Hyponatraemia, hypoglycaemia, creatinine phosphokinase increases The treatment is based on supplementing thyroxine- or triiodo-tironine + HC + respirator Hypercalcemic crisis in primary hyperparathyroidism Hypercalcemic crisis is a suddenly occurring episode of a life-threatening hypercalcaemia. Clinical symptoms of hypercalcemic crisis in primary hyperparathyroidism are mainly caused by severe hypercalcaemia. There is no clear calcemia value which would be tantamount to the hypercalcemic crisis - between 3,5 mmol/l and 4,25 mmol/l (14 mg/dL - 17 mg/dL). Parathyroid hormone (PTH) concentration is significantly increased. It exceeds the upper normal range by 20 times, as it happens in parathyroid (only!) cancer. High concentration of the parathyroid hormone also occurs in ectopic parathyroid hormone secretion, whereas in all the other cases of the crisis the PTH secretion is suppressed. Simultaneous illnesses, however, especially those involving immobilization, may increase the risk of the crisis. Ambulatory care patients most cases of hypercalcaemia are caused by primary hyperparathyroidism, whereas in patients treated in hospital it is usually caused by cancer. Primary hyperparathyroidism is the cause of hypercalcemic crisis in approximately 20% of cases. In almost 75% of cases cancer is the cause of the crisis. In all the remaining cases the crisis is caused by different factors, e.g. hypervitaminosis D, or vitamin D metabolite intoxication. Signs and symptoms: muscular weakness, nausea and vomiting, body weight decrease, tiredness, lethargy and drowsiness, confusion, osteoneuralgia and abdominalgia, polyuria, constipation, coma, polydipsia and renal colic - frequency of 80- 20%. . Hypercalcaemia has an influence on many other systems and organs. In gastrointestinal tract it can result in constipation, excess gastrin secretion, and sometimes even a severe pancreatitis. In kidneys the symptoms are nephrolithiasis, severe or chronic renal insufficiency, renal diabetes and renal tubular acidosis. Psychic disturbances such as anxiety or depression may occur when calcemia exceeds 3 mmol/l. When the concentration exceeds 4 mmol/l hallucinations, confusion and coma may occur. This illness requires an intensive treatment with subsequent parathyroidectomy. It is necessary to supplement liquids, as in the late form of hypercalcaemia the deficiency reaches 3- 6 liters. It is caused by polyuria and vomiting. The deficiency can be supplemented in the first 24 hours with an intravenous infusion of 0.9% NaCl (0.45%). Loop diuretics (furosemide) can be administered only once liquids are supplemented in the vascular bed and if the diuresis is maintained. Once liquids are supplemented, bisphosphonate should be administered (e.g. pamidronate). The dosage should be 60 mg (3,0- 3,4 mmol/l of calcaemia) to 90 mg (above 3,4 mmol/l of calcaemia). Hypercalcaemia should start regressing already after 3 days and normal calcaemia should remain for approximately 3 weeks. Tetany Tetany is caused by muscular and nerves hyperexcitability in many different electrolyte disturbances. In hypoparathyroidism it occurs when the concentration of ionized calcium is low. Total calcium concentration is not adequate here. Nonetheless, in cases when hypocalcaemia level is below 2,25 mmol/l and phosphataemia above 1,60 mmol/l with convulsions, it is necessary to exclude hypoparathyroidism. Tetany symptoms can be aggravated by hypomagnesaemia. The cause is usually hypoparathyroidism as the result of thyroidectomy, parathyroidectomy, or any other surgical intervention of the neck, autoimmune or infiltrative processes, prolonged radiation, toxic agents, abnormal PTH secretion or patient's resistance to PTH or a genetic disorder. Some tetany symptoms are not too intensive, e.g. numbness, distal acroparaesthesia, contractions. There can also be tiredness, depression, anxiety, oversensitivity. Physical examination in the period before tetany can trigger muscular and nerves hyperexcitability and Trousseau sign of latent tetany, which indicates hypocalcaemia. Chvostek sign refers to an abnormal reaction to the stimulation of the facial nerve. When the facial nerve is tapped at the angle of the jaw, the facial muscles on the same side of the face will momentarily contract. Alas, this symptom may occur also in healthy people and in patients with hypomagnesaemia, hypokaliaemia and alkalosis. Symptoms of a more severe tetany are palm and feet muscles contractions, and then the contractions of all the other muscles. In the upper limbs the most contracted muscles are flexors, whereas in lower limbs- extensors. The contractions are bilateral, symmetrical, with remained consciousness. The contractions start with flexor pollicis brevis muscle ("hand of the obstetrician"), then they reach in turn forearm muscles, arm, face, chest, and finally lower limb muscles. The contractions usually pass in reverse order These should not be mistook for general tonic contractions, which occur in severe tetany . There is no relation between the severity of hypocalcaemia and the intensification of tetany, though it occurs most often when calcium concentration is below 1,85 mEq/ l (7,4 mg%). In tetany caused by hypoparathyroidism the most efficient method of treatment is calcium iv infusion. It alleviates the symptoms and prevents convulsions and laryngospasms. It is possible to administer calcium chloride, however it is irritative for veins. An alternative treatment is the infusion of 10- 30 ml of 10% calcium gluconate solution in 5% glucose. Calcium supply should not exceed 100 mg/ hour. The aim is to achieve calcium concentration in blood serum close to the lower range of the norm. It is crucial to be particularly careful with patients to whom digitalis is administered. Among orally administered medicines 1,0- 3,0 g/ 24 hours of calcium should be used (calcium carbonate or calcium chloride due to the highest content of this element), as well as vitamin D metabolites- 2,5 μg/ 24 hours of alfacalcidol in tetany attack, then 0,5- 2,0 μg/ 24 hours or calcitriol . Hyperphosphatemia must be decreased by implementing diet poor in phosphate. 3,0- 6,0 g/ 24 hours of aluminum hydroxide (Alusal) should be administered to limit phosphate absorbance. Phosphate concentration should remain by the upper normal range. Hypomagnesaemia compensation can be achieved by administering 0,3- 1,2 mg/ 24 h of magnesium carbonate. Alkalosis should also be neutralized. Adrenal crisis Adrenal crisis is a state of severe adrenal cortex hormones insufficiency - glucocorticoids and mineral corticoids. It can be caused by primary or secondary adrenocortical insufficiency. In secondary adrenocortical insufficiency symptoms are less intensified. Primary and secondary adrenocortical insufficiency can be differentiated in the process of skin examination. When the illness develops more rapidly, even in the primary form of adrenocortical insufficiency hyper-pigmentation does not occur. The crisis can be caused by the development of simultaneous illness in patients suffering from Addison's disease. In patients who so far have not had any adrenal cortex pathologies the crisis can be caused by autoimmune disease, tuberculosis, cancer metastasis, AIDS, infection (especially meningococcal infection causing WaterhouseFriderichsen syndrome). Adrenal crisis clinical symptoms: muscular weakness, abdominalgia, hypothermia at first and then fever, orthostatic hypotension, vomiting and diarrhea resulting in dehydration. The dehydration results in dry skin, body weight decrease, oliguria, tachycardia, hypoglycaemia causing convulsions. In its most severe form such crisis can result in collapse, hypothermia, loss of consciousness or coma. ACTH and cortisol concentration must be evaluated in the blood serum. The treatment: filling in the vascular bed and supplementing sodium chloride by intravenous saline solution infusion, with the maximum speed, considering the patient's circulatory efficiency. It is usually 2- 3 liters in the first 24 hours and then 3- 4 liters. 50- 100 mg of glucocorticoid (preferably hydrocortisone) should be administered every 6 hours. Next fludrocortisone is administered orally (no parenteral form) to supplement mineral corticoids. The daily dosage of fludrocortisone is 50- 200 μg/ 24 hours and therefore in next stages it should be administered in longer time intervals, e.g. every second day. Nicolaus Copernicus University in Torun L. Rydygier Collegium Medicum in Bydgoszcz THYROID Roman Junik Chair and Dept. of Endocrinology and Diabetology 40 The lobe measures: ►2,5-4 cm in lenght ►1,5-2 cm in width ►1-1,5 cm in thickness ►= 18 cm3 F, 25 cm3 M The weight of gland in the normal individual, as determined by ultrasonic examination, varies depending on dietary iodine intake, age, body weight is approximately 10-20g. Thyroid gland can be displaced at base or under the tongue, or under the hyoid bone. Ectopic gland is also hypoplastic, secreting not enough amounts of thyroid hormones. The thyroid hormones control the metabolism of cells, which is their speed of activity. If there is too little hormones, the body cells work too slowly; too much results in them working too fast. Thyroid hormones regulate the rate of oxygen consumption. This metabolic action influences the utilization of the main components of food: carbohydrates, protein, and fat. negative feedback mechanism The levels of thyroid hormones circulating in the blood are regulated by the thyroid-stimulaing hormone (TSH) produced by the pituitary gland at the base of the brain. If the levels of thyroid hormones fall, TSH stimulates the thyroid to make more hormones. If the levels of thyroid hormones rise above normal, TSH is suppressed. Physical examination Features to be noted include: • thyroid size, • consistency, • nodularity, • tenderness, • fixation. Laboratory evaluation Thus TSH can be used for the first step in the diagnosis of: Overactivity of the thyroid hyperthyroidism (TSH) and underactivity - hypothyroidism (TSH ) Euthyroidism TSH - N fT4 - N fT3 - N Hormone TSH T3 T4 Hyperthyroidism Hypothyroidism Extrathyroid causes for ↑TSH elevation 1. TSH-secreting pituitary tumor = secondary hyperthyroidism 2. Thyroid hormone resistance 3. Assay artifact Extrathyroid causes for ↓TSH suppression 1. Euthyroid sick syndrome- any severe nonthyroidal illness 2. First trimester of pregnancy (due to hCG secretion) 3. Treatment of hyperthyroidism – TSH remains suppressed for several weeks 4. Treatment with high doses of glucocorticoids, dopamine, somatostatin (analogues) 5. Secondary hypothyroidism, caused by hypothalamic-pituitary diseases. Anti-thyroid antibodies and thyroid disease Healthy people Graves’ disease Hashimoto’s thyroiditis TPO TG TRAb (TBII) 10-30% 2% undetectable 70-80% majority 30-50% 70-100% stimulating majority 10-20% blocking Thyroglobulin 1. Serum Tg levels are increased in all types of thyrotoxicosis except thyrotoxicosis factitia caused by self-administration of thyroid hormone. 2. The main role for Tg measurement is in the follow-up of thyroid cancer patients. After total thyroidectomy and radioablation Tg level should be undetectable; measurable levels (>10ng/mL) suggest incomplete ablation or recurrent cancer. Thyroid imaging Radio-isotope thyroid scan In this investigation a radio-isotope, either technetium or iodine, is given that is taken up by the thyroid gland. The gland becomes temporarily radioactive and this is charted by a counter placed over the neck. A record of the uptake called a scintigram can be charted on X-ray film or in colour on paper. Radionuclide imaging 123I, 131I or technetium Tc 99 pertechnetate (99mTc) is useful for determining the functional activity of thyroid gland. This is useful: To define areas of increased or decreased function within the thyroid, which helps to recognise the cause of the thyrotoxicosis To detect retrosternal goitre To detect ectopic thyroid tissue To detect functioning metastases of thyroid carcinoma A biopsy (Fine Needle Aspiration Biopsy, FNAB) is the removal of a small amount of fluid or tissue from the thyroid by needle insertion for further microscopic examination. There are two types of biopsies: -fine needle aspiration -a coarse (large) needle biopsy. Both types are safe and can be done in the physician's office. FNAB is considered the best method for differentiation of benign from malignant thyroid disease – diagnostic in ±80%. Nontoxic goiter Etiology Iodine deficiency or excess Goitrogens in the diet Thyroiditis (Hashimoto, subacute) Graves’ disease Inherited defect in thyroidal enzymes necessary for T4 and T3 biosynthesis 6. Neoplasm, benign or malignant 7. Generalized resistance to thyroid hormone (rare) 1. 2. 3. 4. 5. Nontoxic goiter Nontoxic goiter is noncancerous hyperthrophy of the thyroid with normal thyroid function (euthyroid). That means that a patient has no evidence, either clinically or on laboratory testing of hyperthyroidism, hypothyroidism or inflammation Diffuse nontoxic goiter= simple Nontoxic (multi)nodular goitre Endemic goiter - when affects >5% of the population, caused by iodine deficiency Sporadic goitre - in nonendemic regions Symptoms and Signs The patients may have a history of low or excess iodine intake or overingestion of food goitrogens. In the early stages, the goiter is soft, symmetric and smooth Later, multiple nodules and cyst may develop Symptoms and Signs Pressure symptoms, particulary on moving the head upward or downward: difficulty in swallowing, breathing Pemberton sign: facial flushing and dillation of cervical veins on lifting the arms over the head hoarsness (vocal cord paralysis) Treatment 1. Surgery 2. Radio-iodine treatment 3. Medical treatment Surgery Surgery is indicated for patients with goitre that: 1. intrathoracic 2. gives local compression symptoms 3. with nodule with FNAC suspicious of malignancy 4. that cause cosmetic disfigurement As a rule a near-total thyroidectomy is performed Complications of thyroidectomy Immediate Recurent laryngeal nerve damage Hypoparathyroidism Hypothyroidism Keloid formation Hypothyroidism It is a clinical syndrome resulting from a deficiency of thyroid hormones, which in turn results in a generalized slowing down of metabolic processes. More prevalent in elderly women (up to 5%). Cretinism means hypothyroidism dating from birth and resulting in marked developmental abnormalities including mental retardation. Myxoedema refers to the accumulation of mucopolysaccharides (glycosaminoglycans) in intracellular spaces, particularly in skin and muscles, leading to thickening of the facial features and doughy induration of the skin. It occurs in severe hypothyroidism. Hypothyroidism may be classified as: 1. 2. 3. 4. Primary (thyroid failure) Secondary (to pituitary TSH deficit) Tertiary (due to hypothalamic deficiency of TRH) Peripheral resistance to the action of thyroid hormones Hypothyroidism can also be classified as: A/ Goitrous B/ Nongoitrous Primary hypothyroidism (about 95%) Inability to synthesize adequate quantities of thyroid hormones causes hypersecretion of TSH (elevation in serum TSH) and goitre. If this compensatory response is inadequate, goitrous hypothyroidism ensues (e.g. Hashimoto`s disease). Main clinical features: Early symptoms (non-specific): chronic fatigue lethargy inability to concentrate constipation coldness, cold intolerance menstrual irregularities, menorrhagia, infertility (hypothyroidism impairs the conversion of estrogen precursors to estrogens, resulting in altered FSH and LH secretion and in anovulatory cycles) stiffness and cramping of the muscles muscle weakness paresthesias. Main clinical features: Later symptoms: physical slowing psychiatric symptoms: mental slowing, apathy and withdrawal, depression, or agitation (“myxedema madness”), emotional instability, paranoid psychosis huskiness of voice puffiness of face and eyes pallor dry hair dry skin loss of hair decrease of appetite increase of weight Physical examination – main signs: sinus bradycardia delayed reflexes (normal muscular contraction, slow relaxation) coarse, dry and brittle hair rough, dry, cool skin yellowish colour of the skin (reduced conversion of carotene to vitamin A and increased blood levels of carotene) puffy face and hands hoarse, husky voice obesity goitre or without goiter Laboratory diagnosis of hypothyroidism : Thyroid function tests: Primary hypothyroidism 1. ↓T4 subnormal 2. T3 normal or subnormal 3. ↑TSH elevated 4. Positive test for thyroid autoantibodies suggests underlying Hashimoto`s thyroiditis Management 1. Confirm the diagnosis 2. Provide appropriate patient education 3. Refer the patient where appropriate 4. Exclude co-existing hypoadrenalism and ischemic heart disease before T4 replacement Note: Treatment as primary hypothyroidism when hypopituitarism is the cause may precipitate adrenal crisis. In pituitary hypothyroidism glucocorticoid replacement is essential. Thyroid medication 1. Hypothyroidism is treated with levothyroxine (T4). Intracellularly, levothyroxine is converted to T3, so that both hormones become available even though only one is administered. 2. Doses of levothyroxine in adults range from 50 to 200g (1-2μg/kg/daily), according to the patient’s age and body weight once daily, ½ hour before breakfast. Levothyroxine has a sufficiently long half-life (7 days) so that if the patient is unable to take medications by mouth for a few days, omitting levothyroxine therapy will not be detrimental. The parenteral dose of T4 is about 7580% of the usual oral dose. Note: Start with low doses (12,5-25-50 μg daily) in elderly and ischemic heart disease!!! Avoid overdosage. Monitor TSH levels monthly at first. As euthyroidism is achieved, monitoring may be less frequent, e.g. once a year. During pregnancy and lactation the dose of T4 must be increased. Older patients metabolize T4 more slowly, and the dose will gradually decrease with age. THYROTOXICOSIS Thyrotoxicosis == clinical, physiological and biochemical findings that result when the tissues are exposed to, and respond to excess thyroid hormones. Hyperthyroidism = hyperfunction of the thyroid that may lead to thyrotoxicosis VARIETIES OF THYROTOXICOSIS 1/ Associated with thyroid hyperfunction = overproduction of hormones by the thyroid gland itself excessive production of TSH (pituitary tumour, rare) abnormal thyroid stimulator (of extrapituitary origin) Graves` disease Trophoblastic tumour intrinsic thyroid autonomy Hyperfunctioning adenoma Toxic multinodular goiter VARIETIES OF THYROTOXICOSIS 2/ Not associated with thyroid hyperfunction Disorders of hormone storage (an excess of preformed hormone leaks from the gland owing to the presence of inflammatory disease) •Subacute thyroiditis •Chronic thyroiditis with transient thyrotoxicosis (new hormone formation is decreased – suppression of TSH) Extrathyroid source of hormones • Thyrotoxicosis factitia • “hamburger toxicosis” = ingestion of meat contaminated with animal thyroids • ectopic thyroid tissue - struma ovarii - functioning follicular Ca GRAVES` DISEASE = disorder with three major manifestations which do not need to appear together and are independent of one another: 1/ hyperthyroidism with diffuse goiter 2/ ophthalmopathy 3/ dermopathy Graves` disease is relatively common, more frequent in women (in nongoitrous regions F:M=7:1), especially in the third and fourth decade of life. Genetic factors connected with haplotypes HLA-B8 and DR3 play an important role → familial predisposition. Pathogenesis of Graves’ disease An abnormal plasmic thyroid stimulators with prolonged duration of action relative to that of TSH. They belong to immunoglobulins of the IgG class elaborated by lymphocytes of patients with Graves` disease These factors represent antibodies TSI (thyroid stimulating immunoglobulins) directed against the thyroid TSH receptor (TRAb) that mediate the thyroid stimulation → hyperthyroidism and goiter. Pathogenesis of Graves` disease The pathogenesis of the ophthalmic component is more enigmatic. Proposed mechanism is the development of antibodies (TSH-R-Ab, TRAb) against specific antigens in the extraocular muscles. The pathogenesis of the dermopathy is still unclear. CLINICAL MANIFESTATIONS Manifestations of thyrotoxicosis (not typical for Graves` disease only) vary in intensity with the severity and duration of the illness, the age of the patient and the presence of disease in other organs, such as the heart. These are: Nervousness Emotional lability Inability to sleep Tremors Frequent bowel movements Excessive sweating Heat intolerance Weight loss despite a well-maintained or increased appetite CLINICAL MANIFESTATIONS Proximal muscle weakness with loss of strength → difficulty in climbing stairs Oligomenorrhea or amenorrhea Warm and moist skin with a velvety texture Dyspnea Palpitations Enhancement of angina pectoris or cardiac failure in older patients Palmar erythema Fine and silky hair Fine tremor of the fingers and tongue Hyperreflexia Ocular signs (result from sympathetic overstimulation and usually subside when the thyrotoxicosis is corrected; they are called noninfiltrative ophthalmopathy and have to be distinguished from the infiltrative ophthalmopathy characteristic for Graves` disease): Stare with widened palpebral fissures Infrequent blinking Lid lag Failure to wrinkle the brow on upward gaze Cardiovascular findings: - Wide pulse pressure - Tachycardia - Arrhythmias (atrial fibrillation) - Systolic murmurs - Increased intensity of the apical first sound - Cardiac enlargement Manifestations of Graves` disease •Diffuse toxic goiter (the most common) = the thyroid gland is diffusely enlarged, soft and vascular, may be asymmetric and lobular. A bruit over the gland usually signifies that the patient is thyrotoxic. An enlarged pyramidal lobe of the thyroid may be palpable. Dermopathy – thickening of the dermis, which is infiltrated with lymphocytes and mucopolysaccharides. Usually occurs over the dorsum of the legs or feet and is termed pretibial myxedema. The skin is: - raised - thickened - has a peau d`orange appearance - may be pruritic and - hyperpigmented Manifestations of Graves` disease Ophthalmopathy – an inflammatory infiltration of the orbital contents, exclusive of the globe. The orbital musculature is often enlarged due to infiltration with lymphocytes, mucopolysaccharides and edema → the increased volume of the orbital contents → protrusion of the eyeballs. Clinical signs are: - Stare - Lid lag - Lid retraction - Proptosis of varying degrees with ophthalmoplegia - Chemosis - Conjunctivitis - Periorbital swelling - Complications of corneal ulceration - Optic neuritis - Optic atrophy Exophthalmic ophthalmoplegia refers to the ocular muscle weakness → impaired upward gaze, convergence and strabismus with varying degrees of diplopia. Exophthalmos may be unilateral or bilateral. Management The aim : - Control the hyperthyroidism - Sustain remission Treatment of Graves’ Disease There are three main methods, not mutually exclusive: 1. Antithyroid Drug Therapy 2. Radioactive Iodine Therapy 131I 3. Surgical Treatment Antithyroid drugs 1. Imidazole: carbimazole methimazole=thiamazole (Metizol 5mg, Thyrozol 5, 10,20mg, Favistan i.v. 40 mg) Carbimazole is a pro-drug as after absorption it is converted to the active form methimazole 2. Thioamide propylothiouracil (Thyrosan 50 mg) Antithyroid Drug Therapy Anti-thyroid drugs suppress the ability of the thyroid to make thyroid hormones. Methimazole prevents the thyroid peroxidase enzyme from coupling and iodinating the tyrosine residues on thyroglobulin, hence reducing the production of the thyroid hormones. Propylothiouracil also partially inhibits the conversion of T4 to T3. Antithyroid drug therapy is generally started with large divided doses. (M-40mg, P-400mg) When the patient becomes clinically euthyroid, maintenance therapy may be achieved with lower single morning dose. Major side effects Fortunately, the major side effects of antithyroid drugs are very rare. Allergic reaction to antithyroid involve either a rash (about 5% of patients) or agranulocytosis 0,5%. The rash can be managed by simply administering antihistamines. Agranulocytosis is characterized by a decrease in the production of white blood cells. This condition is extremely serious, but affects only one out of every 200 to 500 people who take an antithyroid drug. Agranulocytosis is more likely to occur within the first three months of starting treatment with an antithyroid drug. If patient develops a sore throat, fever, or other signs or symptoms of infection, they should stop medication and immediately contact doctor. Serious and potentially life threatening infections, or even death, can occur before agranulocytosis resolves. However, once the antithyroid drug is stopped, agranulocytosis usually resolves within a 2-3 weeks. Radioactive Iodine Therapy 131I Radioactive iodine (RAI) is often chosen for treatment of hyperthyroidism because of its simplicity: it is given in a single dose. In the USA it is the preferred treatment for most GD patients. How Radioactive Iodine Treatment Works RAI treatment is based on the fact that the thyroid actively accumulates iodine, which it uses to produce thyroid hormones required for normal body function. This RAI is like the iodine found in foods, except that it releases beta particle, which creates its therapeutic action. While in the thyroid gland, the RAI disrupts the function of some of the thyroid cells - the more radioactive iodine given, the more cells cease to function. As the cells stop functioning, excessive amounts of thyroid hormones are no longer produced, and symptoms of hyperthyroidism begin to disappear. Precautions Some precautions are necessary because of the small amount of radiation that emanates from the neck where the RAI is stored for a few days after treatment. While this radiation is beneficial for the person being treated, precautions are needed to reduce the radiation families and friends are exposed to. Surgical Treatment Subtotal thyroidectomy is the treatment of choice for patient with large gland or multinodular goiter. The patient is prepared with antithyroid drug until euthyroid. In addition, 10 days before operation patient is given solution of potassium iodide to diminish the vascularity of the gland and to simplify surgery. TOXIC NODULAR GOITER This term means independence from TSH stimulation in one or more areas of the gland. Because it arises in long-standing simple goiter, toxic multinodular goiter is a disease of the aging or elderly. The clinical presentation differs from that in Graves` disease. Ophthalmopathy is rare. The degree of thyrotoxicosis is often less severe than in Graves` disease, although its physiologic impact on specific organs may be great – especially on the cardiovascular system (arrhythmias, congestive heart failure). Thyroiditis 1. Acute thyroiditis 2. Subacute thyroiditis 3. Chronic thyroiditis Acute (pyogenic) thyroiditis It is antecedent by a pyogenic infection elsewhere with septicaemia or acute endocarditis. Staph. aureus, streptococci, E. coli, tuberculosis, fungal Thyroid function is usually normal. Acute thyroiditis The signs are: local pain and tenderness of the thyroid swelling of the thyroid redness of the overlying skin warmth of the skin constitutional signs of infection Subacute thyroiditis (granulomatous, giant cell, de Quervain`s thyroiditis) It is viral in origin (mumps virus, coxackievirus, adenoviruses). Subacute thyroiditis The symptoms are: moderate thyroid enlargement pronounced asthenia malaise fever pain and/or tenderness (especially on swallowing) over the thyroid, lower jaw or ear Physical findings include: tenderness and nodularity of the thyroid, which may be unilateral but usually involves whole gland. There are no signs of local redness or heat suggestive of abscess formation. Histological features include many large phagocytic cells, including giant cells. Early, many patients are mildly thyrotoxic. Thyroid radioactive iodine uptake (RAIU) is extremely low. The erythrocyte sedimentation rate (ESR) is markedly elevated (50-100/h). Thyroid autoantibodies are usually not detectable in serum. Later the patient may pass through a hypothyroid phase (T4 and T3 decrease and TSH increases) and returns to normal thyroid function (RAIU rises reflecting recovery of the gland). Subacute thyroiditis usually resolves completely over weeks or months. Treatment In the acute phase treatment is based on nonsteroid anti-inflammatory drugs eg. acetaminophen 0,5 g four times daily. Avoid high-dose aspirin - competitively displaces thyroid hormone from its binding protein. A short course of glucocorticoid such as prednisone 20mg 3 times daily, for 7-10 days, may be necessary to reduce the inflammation. Antithyroid drugs are not indicated. Beta-blockers eg.propranolol can be used to control symptoms. Chronic thyroiditis Hashimoto`s disease, (AITD) (autoimmune thyroiditis, lymphocytic thyroiditis). It is an autoimmune thyroiditis, which is a common cause of hypothyroidism and sometimes goitre. It occurs most frequently in women of middle age. Lymphocytes become sensitized to thyroid antigens and autoantibodies are formed that react with these antigens. Chronic thyroiditis The three most important thyroid autoantibodies are: 1. thyroglobulin antibody (Tg Ab) 2. thyroid peroxidase antibody (TPO Ab), formerly called microsomal antibody 3. TSH receptor blocking antibody (TSH-R Ab [block]). Chronic thyroiditis Early in the disease the patient is metabolically normal (sometimes thyrotoxic); as the disease progresses, thyroid failure, at first subclinical, becomes evident (↑TSH increases, ↓T4 decreases, T3 normal or decreases). Chronic thyroiditis Hashimoto`s disease may be associated with other autoimmune diseases such as: DM1, pernicious anaemia, adrenocortical insufficiency, myasthenia gravis, idiopathic hypoparathyroidism, and vitiligo. Features are: bilateral, painless goitre classically described as firm and rubbery patients may be hypothyroid or euthyroid Diagnosis is confirmed by a strongly positive serum antithyroid antibody titre and (TPOAb)/or fine needle aspiration cytology (lymphocytic infiltration of the gland and the presence of Hurthle cells) or US. Riedel`s thyroiditis It is a disorder in which intense fibrosis of the thyroid, involving overlying muscle and surrounding structures, leads to induration of the tissue of the neck. It requires being distinguished from thyroid neoplasia. Thyroid Cancer Most thyroid nodules are benign and it is important to identify those that are likely to be malignant. Scanning techniques 123I, 131I or 99mTc More likely benign „hot nodule” More likely malignant „cold nodule” USG More likely malignant nodule Solid, hypoechogenic Diameter > 10 mm Central vascularization Microcalcification Margin (rim) not continuous or irregular Wider than taller How is cancer of thyroid diagnosed? The diagnosis is made on the basis of clinical suspicion and confirmed by fine-needle aspiration (FNAB). If this is inconclusive, the diagnosis may be confirmed only by surgery. Malignant thyroid tumors 1. Differentiatied Papillary carcinoma 75% Follicular carcinoma 15% Medullary carcinoma 5% (develop from C cells) 2. Undifferentiated (anaplastic)carcinomas 3% 3. Miscellaneous 1% Papillary Carcinoma Papillary ca has a bimodal frequency with peaks occurring in the second or third decade and again in later life. Usually presents as a nodule: firm solitary “cold” on isotope scan solid on ultrasound clearly different from the rest of the gland in multinodular goiter- a dominant nodule, larger and firmer with enlarged cervical nodes - 10% These cancers usually extend by intraglandular metastasis and by local lymph node invasion. They are usually nonencapsulated, grow very slowly, but may become more aggressive in older patients and convert to undifferentiated or anaplastic carcinoma. In later stages, they can spread to the lungs or bones. Management • Total thyroidectomy. (For lesions of 1 cm or less, lobectomy with isthmectomy is recommended). • Postoperative radioiodine therapy – ablation 131I if there is evidence of residual radioactive iodine uptake in the neck or elsewhere. • Levothyroxine 150-300 ug daily (2.0-2.5 ug/kg/d), to suppress serum TSH to the level< 0.1 mU/L • Follow-up at intervals of 6-12 months : examination of the neck, chest x-ray, thyroid ultrasound, 131I whole body scan serum thyroglobulin negligible (<2 ng/mL) – a rise in serum thyroglobulin suggests recurrence of thyroid cancer