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THE THYROID GLAND HYPERTYROIDISM THE THYROID GLAND The thyroid secretes primarily Thyroxine / T4 / T4 is probably not metabolically active until converted to T3 (T4 = prohormone) ~85% of T3 is produced by monodeiodination of T4 THE THYROID GLAND T3 and T4 circulate in plasma are almost entirely (>99,9%) bound to transport proteins (mainly TBG, less TBPA and albumins) Only free hormones exert its metabolic action It is better to measure the concentration in plasma FT3 or FT4 Patterns of thyroid function test results in patients with hyperthyroidism Conventional hyperthyroidism (95% of cases): FT4 ; FT3 ; TSH or undetectable T3-hyperthyroidism (5% of cases): FT4 ↔; FT3 ; TSH or undetectable Subclinical hyperthyroidism: FT4 ↔; FT3↔; TSH or undetectable Not-thyroidal illness (e.g. myocardial infarction or pneumonia): Decreased peripherial conversion of T4 to T3. Alterations in the binding proteins. Alterations in the affinity of binding proteins for thyroid hormones. ↓TSH levels as a results of the illness itself or the use of drugs (e.g. dopamine or corticosteroids). ↑TSH into the hypothyroid range during convalescence. THYROTOXICOSIS Hypermetabolic state caused by thyroid hormone excess at the tissue level HYPERTHYROIDISM Increased thyroid hormones synthesis and secretion All patients with hyperthyroidism have thyreotoxicosis Not all patients with thyreotoxicosis are hyperthyroid PREVALENCE Females: Males: ~20/1000 ~4/1000 AETIOLOGY It is important to identify the cause of hyperthyroidism in order to prescribe appropriate treatment Causes of thyrotoxicosis common types With low RAIU With high RAIU Graves diseases (60-90%) Multinodular goitre (14%) Autonomously functioning solitary thyroid nodule (5%) Iodine-induced thyrotoxicosis Thyroiditis subacute (3%) silent (painless) post-partum Iodine-induced thyrotoxicosis drugs (e.g. amiodarone) radiografic contrast media iodine prophylaxis programme Causes of thyrotoxicosis uncommon types With high RAIU With low RAIU Congenital hyperthyroidism TSH-induced hyperthyroidism TSH-secreting adenoma selective pituitary resistance to thyroid hormone Trophoblastic tumors Thyrotoxicosis facticia (0.2%) Metastatic thyroid carcinoma (0.1%) Struma ovarii CLINICAL FEATURES OF HYPERTHYROIDISM Most signs and symptoms are common to all types of thyreotoxicosis; Some of them are specific to defined disease for example: ophthalmopathy pretibial myxoedema thyroid acropathy Graves’ subacute disease thyroiditis thyroid pain tendernees CLINICAL FEATURES OF HYPERTHYROIDISM (according to frequency) SYMPTOMS Nervousness Palptations Increased sweating Haet intolerance Fatigue Weight loss Dyspnea Increased appetite Eye symptoms Friable hair and nails Increased bowel movements Diarrhoea Menstrual disturbances SIGNS Tachycardia Goitre Tremors Skin changes Hyperkinesis Thyroid bruit Lid lag and retraction Ophthalmopathy Atrial fibrillation Onycholisis Localized (pretibial) myxedema Vitiligo Acropathy GRAVES’ DISEASE the most frequent cause of hyperthyroidism Graves’ disease is an autoimmune thyroid disease, characterized by diffuse thyroid enlargement, ophtalmopathy and less frequently dermopathy (pretibial myxedema) and acropathy. It can occur at any age (unusual before puberty and most commonly affects the 30-50- years-old age group) the female/ male ratio ~7 : 1 Graves’ disease - pathogenesis Thyroid antigen-specific T lymphocytes Humoral and cell-mediated immune reactions Infiltration of the thyroid gland by immune effector cells Graves’ disease - pathogenesis Genetic and environmental factors Production of IgG antibodies (thyroid-stimulating immunoglobulins TSI or TSH-receptor antibodies TRAb) Stimulation thyroid hormone production and goitre formation Graves’ disease - pathogenesis Genetic factors: The familial predisposition. The frequent finding of circulating autoantibodies in relatives of Graves’ patients. The high concordance rate in monozygotic twins. The positive association with haplotypes HLA-B8 and DR3 (Caucasians), HLA-B35 (Japonese population), and HLA-Bw46 (Chinese population). Female sex hormones. Graves’ disease - pathogenesis Environmental factors: Iodine Immune-stimulant effect (in areas of iodine defficiency thyroid autoimmune diseases are rare). Cigarettes (assotiation with Graves’ ophtalmopathy influence on immunecompetent cells?). Graves’ disease - pathogenesis Environmental factors: Escherichia coli and Yersinia enterocolitica (antibodies to these microbial antigens cross-reaction with the TSH-receptor hyperthyroidism. Stress (relationship between the onset of hyperthyroidism and a major life event). Graves’ disease - pathogenesis Ophtalmopathy and dermopathy: Pathogenesis is less well understood. Immunologically mediated but TRAb is not implicated. Proliferation of fibroblasts (adipocytes?) within the orbit Increased interstitial fluid content Chronic inflammatory cel infiltrate Swelling of the extra-ocular muscles Rise in retrobulbar pressure Graves’ disease - clinical findings THYROID GLAND: Symmetrically enlarged Firm Thrills and bruits Goiter is absent in 3% of causes Graves’ disease – clinical findings LOCALIZED MYXEDEMA: Pretibial region Raised, light colored or yellow-reddish lesion with orange peel apperance Sometimes pruritus Graves’ disease – clinical findings THYROID ACROPATHY: Swelling and soft tissues of hands feet Clubbing of fingers and toes True ophtalmopathy is specific of Graves’ disease Soft tissue involvement: Lacrimation Burning sensation Redness Photophobia Gritty sensation Proptosis (exophtalmos) and lagophthalmos keratitis Extra-ocular muscle dysfunction diplopia Optic neuropathy blidness Cardiovascular system Tachycardia Palpitations Blood pressure: systolic diastolic THYROCARDIAC SYNDROME Premature heart beats Atrial fibrillation Heart failure and/or angina Alimentary system Increased appetite but weight loss Increased frequency of bowel movements and diarrhea Rarely liver dysfunction Nervous system Nervousness Hyperactivity Anxiety Insomnia Emotional instability Fine tremors Muscles Muscular weakness In most severe cases muscular atrophy Skeletal system Thyrotoxicosis Increased loss of bone osteoporosis Metabolism Increased oxygen consumption Diabetes mellitus may be exacerbated Serum cholesterol plasma triglycerides GRAVES’ DISEASE – DIAGNOSTIC PROCEDURES Labolatory investigation Imaging studies important particularly in the absence of goitre and eye disease Important particularly in diagnostic of Graves’ ophtalmophathy Computed tommography Magnetic resonance LABORATORY INVESTIGNATION Hyperthyroidism Serum concentrations of: TSH: undetectable or FT4: FT3: T3-toxicosis: TSH: undetectable or FT3: FT4: ↔ Graves’ disease: TRAb TPO ATG Imaging studies 24-hour thyroidal radioactive iodine uptake: increased thyroid scan diffuse, homogenous goitre Thyroid ultrasound: enlarged gland hypoechoic pattern increased blood flow Computed tomography and magnetic resonance GRAVES’ DISEASE – TREATMENT General principles of treatment RADIOIODINE MEDICAL Treatments available for Graves’ disease SURGICAL Most treatment regiments are directed at the thyroid, but there is a small place for peripherally acting drugs such as propranolol and ipodate. GRAVES’ DISEASE – TREATMENT Indications for medical treatment Patient preference Small goitre Mild disease Other diseases Children Pregnancy Ophtalmopathy Preoperative Pre-radioiodine Thyrotoxic crisis Relapse after thyroidectomy ANTITHYROID DRUGS THIONAMIDES: Methimazole, Carbimazole, Propylthiouracil Mechanism of actions: Inhibition of thyroid hormone synthesis and secretion PTUinhibition of peripheral conversion of T4 to T3 THIONAMIDES Goal: Permanent remission of hyperthyroidism Limitations: High recurrence rate of hyperthyroidism Possible side effects Factors that may influance antithyroid drug therapy associated with remission Laboratory Modest elevation of Small goitre thyroid hormones Mild disease Low urinary iodine excretion Rapid responce to Low or absent TSH-R9s) antithyroid drugs antibodies at end of Small maintenance dose therapy Female sex Normal responce to TRH at end of therapy Low iodine intake Normal suppression of thyroidal radioiodine uptake at end of therapy Clinical Factors that may influance antithyroid drug therapy associated with relapse Laboratory Major elevation of thyroid Large goitre hormones Vascular goitre High urinary iodine excretion Severe disease Raised TSH-R(s) Slow responce to antibodies at end of antithyroid drugs therapy Large maintenance dose Absent responce to TRH at end of therapy Male sex Impaired or absent High iodine intake suppression of thyroidal radioiodine uptake at end of therapy Clinical THIONAMIDES Side effects (overall frequency <5%) Nausea Vomiting Pruritis Skin rash Urticaria Loss of taste Mild leukopenia (12 – 25%) Agranulocytosis (0.1 – 0.5%) Aplastic anemia Thrombocytopenia Cholestasis Hepatocellular necrosis Lupus-like syndrome Nephrotic syndrome GRAVES’ DISEASE – TREATMENT Indications for surgical treatment Experienced thyroid surgeon avaliable Patient preference Adults up to 40 years Severe disease Nodular goitre Large goitre Relapse after drug treatment SURGICAL TREATMENT PARTIAL THYROIDECTOMY Mechanism of action removal of tissue responsible for excessive thyroid hormone synthesis PARTIAL THYROIDECTOMY Goal thyroid ablation, i.e. hypothyroidism Contraindications systemic contraindications to surgery PARTIAL THYROIDECTOMY - COMPLICATIONS EARLY Recurrent laryngeal nerve palsy Superior laryngeal nerve palsy Haemorrhage Hypoparathyroidism Pneumothorax Thyroid crisis Damage to thoracic drug Damage to carotic artery Damage to jugular vein LATE Cheloid scar Tethered scar Hypothyroidism Recurrence of hyperthyroidism Recurrent upper pole nodules GRAVES’ DISEASE – TREATMENT Indications for radioiodine therapy Patient preference Poor-compliance with antithyroid drugs Patients over 40 years Recurrence after thyroidectomy Severe uncontrolled disease Large goitre Unco-operative patients Presence of other disease(s) RADIOIODINE THERAPY Mechanism of action Destruction of thyrocytes by β-radiation Goal thyroid ablation, i.e. hypothyroidism Contraindications pregnancy RADIOIODINE THERAPY Complcations Permanent hypothyroidism Transient hypothyroidism Thyroiditis Sialadenitis Thyrotoxic crisis Nodule formation Possible exacerbation of ophtalmopathy (preventable by glucocorticoids) GRAVES’ DISEASE – TREATMENT Other drugs Β-adrenergic antagonists (e.g. Propranolol) Inorganic iodide Potassium perchlorate Glucocorticoids GRAVES’ DISEASE – TREATMENT OF OPHTHALMOPATHY Mild ophthalmopathy Guanethidine or β-adrenergic eye drops (lid retraction) Methylcellulose eye drops (lacrimation, burning sensation) Sunglasses (photophobia) Nighttime tapering of eyes (lagophthalmos) Prisms (mild diplopia) Severe ophthalmopathy High-dose glucocorticoids (active ophthalmopathy) Orbital radiotherapy (active ophthalmopathy) Orbital decompresion (active or inactive ophthalmopathy) Rehabilitative surgery: eye muscles, eyelids (to be performed at least 6 months after rendering ophthalmopathy stable and inactive with other treatments) Immunosuppressive drugs, somatostatin analogues, intravenous immunoglobulins, plasmapheresis. THYROTOXIC STORM RARE BUT VERY SERIOUS COMPLICATION OF HYPERTHYROIDISM Severe manifestations of hypermetabolic (fever, profound sweating, dehydration, restlessness, insomnia) In patients with not diagnosed or inadeguately treated hyperthyroidism INFECTIONS SURGERY THYROTOXIC STORM TRAUMAS THYROTOXIC STORM TREATMENT High doses of thionamide Iodide or iodinated contrast agents Glucocorticoids β-adrenergic antagonists The treatmnent of underlying nonthyroidal illness Correction of dehydration Normalisation of body temperature Plasmapheresis or peritoneal dialysis TOXIC ADENOMA An autonomously functioning, benign thyroid nodule causing thyrotoxicosis >10% Iodine-deficient areas FREQUECY Iodine-sufficient areas ≤10% TOXIC ADENOMA Solitary nodule in: otherwise normal thyroid gland goiter Pathogenesis: Somatic mutations in the gene encoding the TSH receptor constitutive activation of TSH receptor TOXIC ADENOMA Smptoms and signs of thyrotoxicosis Ophthalmopathy, localized myxedema and acropachy are absent Thyroid scan Prevalent tracer uptake in the nodule („hot nodule”) Treatment Radioiodine or surgery Antithyroid drugs only for preparation of definitive treatment TOXIC MULTINODULAR GOITER Multiple hyperfunctioning thyroid nodules or areas of autonomously functioning thyroid follicles Commonly found in older patients with long-standing multinodular goiter. UNUSUAL FORMS OF THYROTOXICOSIS TSH-INDUCED HYPERTHYROIDISM TSH-secreting Selective pituitary resistence pituitary adenoma (280 cases so far described) TSH or ↔; FT4 ; FT3 TSH α-subunit TSH α-subunit / TSH>1 TSH or ↔; FT4 ; FT3 TSH α-subunit ↔ TSH α-subunit / TSH<1 UNUSUAL FORMS OF THYROTOXICOSIS Thyrotoxicosis factitia Clinical and biochemical picture is typical of thyrotoxicosis Goiter is absent RAIU is very low/suppressed Serum thyroglobulin – very low or undetectable Congenital hyperthyroidism Germline mutations of the TSH-R gene Constitutional activation in all thyroid follicular cells UNUSUAL FORMS OF THYROTOXICOSIS Metastatic thyroid carcinoma Struma ovarii Follicular thyroid arcinoma Metastases to lung and bone Thyrotoxicosis (rarely) Functioning thyroid tissue within an ovarian teratoma or dermoid UNUSUAL FORMS OF THYROTOXICOSIS Trophoblastic tumors High serum and urine concentrations of β-subunit of chorionic gonadotropin stimulation of TSH receptor