THE THYROID GLAND

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 NEGATIVE FEEDBACK

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

AETIOLOGY PREVALENCE It is important to identify the cause of hyperthyroidism in order to prescribe appropriate treatment Females: ~20/1000 Males: ~4/1000

With high RAIU Graves diseases (60-90%) Multinodular goitre (14%) Autonomously functioning solitary thyroid nodule (5%) Iodine-induced thyrotoxicosis With low RAIU Thyroiditis subacute (3%) silent (painless) post-partum Iodine-induced thyrotoxicosis drugs (e.g. amiodarone) radiografic contrast media iodine prophylaxis programme Causes of thyrotoxicosiscommon types

With high RAIU Congenital hyperthyroidism TSH-induced hyperthyroidism TSH-secreting adenoma selective pituitary resistance to thyroid hormone Trophoblastic tumors With low RAIU Thyrotoxicosis facticia (0.2%) Metastatic thyroid carcinoma (0.1%) Struma ovarii Causes of thyrotoxicosisuncommon types

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 thyroid pain tendernees Graves’ disease subacute thyroiditis

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 CLINICAL FEATURES OF HYPERTHYROIDISM(according to frequency)

GRAVES’ DISEASEthe 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 immune-competent 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  Redness • Burning sensation  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

Nervousness Anxiety Emotional instability Hyperactivity Insomnia Fine tremors Nervous system Muscles • Muscular weakness • In most severe cases muscular atrophy

Skeletal system osteoporosis Increased loss of bone Thyrotoxicosis Metabolism • Increased oxygen consumption • Diabetes mellitus may be exacerbated • Serum cholesterol  plasma triglycerides

Labolatory investigation  important particularly in the absence of goitre and eye disease Imaging studies  Important particularly in diagnostic of Graves’ ophtalmophathy  Computed tommography Magnetic resonance GRAVES’ DISEASE –DIAGNOSTIC PROCEDURES

Hyperthyroidism Serum concentrations of: TSH: undetectable or  FT4:  FT3:  T3-toxicosis: TSH: undetectable or  FT3:  FT4: ↔ Graves’ disease: TRAb   TPO  ATG  LABORATORY INVESTIGNATION

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 Treatments available for Graves’ disease SURGICAL MEDICAL Most treatment regiments are directed at the thyroid, but there is a small place for peripherally acting drugs such as propranolol and ipodate.

Patient preference Small goitre Mild disease Other diseases Children Pregnancy Ophtalmopathy Preoperative Pre-radioiodine Thyrotoxic crisis Relapse after thyroidectomy GRAVES’ DISEASE – TREATMENT Indications for medical treatment

ANTITHYROID DRUGS THIONAMIDES: Methimazole, Carbimazole, Propylthiouracil Mechanism of actions: Inhibition of thyroid hormone synthesis and secretion PTUinhibition of peripheral conversion of T4 to T3

THIONAMIDES Goal: • Permanent remission of hyperthyroidism Limitations: • High recurrence rate of hyperthyroidism • Possible side effects

Clinical Small goitre Mild disease Rapid responce to antithyroid drugs Small maintenance dose Female sex Low iodine intake Laboratory Modest elevation of thyroid hormones Low urinary iodine excretion Low or absent TSH-R9s) antibodies at end of therapy Normal responce to TRH at end of therapy Normal suppression of thyroidal radioiodine uptake at end of therapy Factors that may influance antithyroid drug therapyassociated with remission

Clinical Large goitre Vascular goitre Severe disease Slow responce to antithyroid drugs Large maintenance dose Male sex High iodine intake Laboratory Major elevation of thyroid hormones High urinary iodine excretion Raised TSH-R(s) antibodies at end of therapy Absent responce to TRH at end of therapy Impaired or absent suppression of thyroidal radioiodine uptake at end of therapy Factors that may influance antithyroid drug therapyassociated with relapse

Nausea Vomiting Pruritis Skin rash Urticaria Loss of taste Side effects (overall frequency <5%) THIONAMIDES • Mild leukopenia (12 – 25%) • Agranulocytosis (0.1 – 0.5%) • Aplastic anemia • Thrombocytopenia • Cholestasis • Hepatocellular necrosis • Lupus-like syndrome • Nephrotic syndrome

Experienced thyroid surgeon avaliable Patient preference Adults up to 40 years Severe disease Nodular goitre Large goitre Relapse after drug treatment GRAVES’ DISEASE – TREATMENT Indications for surgical 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

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 PARTIAL THYROIDECTOMY- COMPLICATIONS LATE • Cheloid scar • Tethered scar • Hypothyroidism • Recurrence of hyperthyroidism • Recurrent upper pole nodules

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) GRAVES’ DISEASE – TREATMENT Indications for radioiodine therapy

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)

Β-adrenergic antagonists (e.g. Propranolol) Inorganic iodide Potassium perchlorate Glucocorticoids GRAVES’ DISEASE – TREATMENT Other drugs

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) GRAVES’ DISEASE – TREATMENT OF OPHTHALMOPATHY

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

High doses of thionamide Iodide or iodinated contrast agents Glucocorticoids β-adrenergic antagonists The treatmnent of underlying non-thyroidal illness Correction of dehydration Normalisation of body temperature Plasmapheresis or peritoneal dialysis THYROTOXIC STORM - TREATMENT

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

THE THYROID GLAND