Thyroid Disorders Pitfall of Diagnosis & Management. Dr. KW Lo Division of Endocrinology & Diabetes HK Sanatorium & Hospital

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1 Thyroid Disorders Pitfall of Diagnosis & Management Dr. KW Lo Division of Endocrinology & Diabetes HK Sanatorium & Hospital

2 What Is the Thyroid A small butterfly-shaped gland (~20 gm in an adult) located in the neck in front of the trachea Producing thyroid hormones (T4 and T3), chemicals that travel through the blood to every part of the body Thyroid hormones tell the body how many calories we burn, how warm we feel, and how much we weigh

3 Mechanism of Thyroid Hormones Action at the Cell Level Binds to high affinity T3 nuclear receptor complex, which stimulates the formation of mrna sequences and subsequently brings about new protein synthesis Binds to receptors for T3 at the mitochondrial level; stimulation of oxygen consumption and increase in BMR Enhance sympathetic activities

4 Physiological Effects of Thyroid Hormones (1) Skin & connective tissue: important in the integrity of the collagen, essential for normal hair growth Respiratory: regulation of ventilation, affect respiratory muscle function CVS: affect cardiac contractility, velocity of muscle shortening and the rate of isometric tension development Neuromuscular: required for normal brain morphology and histogenesis,, and deficiency in neonatal life results in irreversible brain damage

5 Physiological Effects of Thyroid Hormones (2) GI and Kidney: affect the motility of the GI tract; inability to clear free water if no thyroid hormones Endocrine: affect growth and sexual development, control menstrual regularities and fertility, affect metabolism of steroid hormones in the liver Intermediary metabolism: stimulate lipolysis, enhance hepatic gluconeogenesis,, stimulate protein synthesis and breakdown, increase bone turn over Erythropoiesis: enhance red cell formation

7 Production of T 41 T 31 and rt 3. The principal thyroid gland secretion is T 41 85% of which is monodeiodinated by peripheral tissues to T 3 and rt 3. Under normal conditions only small amounts of T 3 and rt 3 are derived from thyroidal secretion, a discovery that has led to the concept of T 4 as a prohormone.. In nonthyroidal illness peripheral conversion of T 4 to rt 3 is enhanced leading to a reduction in serum T 3 concentration ( sick( euthyroid ). The physiological significance of this shift in T 4 metabolism is not well understood.

8 Serum Proteins that Transport Thyroid Hormones* Proteins T 4 Bound (%) Thyroxine-binding globulin (TBG) 75 Thyroxine-binding prealbumin (TBPA) 20 Albumin 5 *The amount of free and metabolically active hormone is extremely small, accounting for about 0.03% of circulating T4 and 0.3% of circulating T3

Thyroid Function Tests: The modern assay of TSH Diagram of principles involved in immunoradiometric assay for thyroid-stimulating hormone (TSH: thyrotropin).

9 Thyroid Function Tests: The modern assay of TSH Diagram of principles involved in immunoradiometric assay for thyroid-stimulating hormone (TSH: thyrotropin). Assay monoclonal antibody linked to a solid phase support.(photograph courtesy of Boots-Celltech Diagnostic, Limited, Product Information, Slough, United Kingdom.)

10 Proposed strategy for investigation of thyroid function in patients with suspected thyroid disease. FT3 = free triiodothyronine; ; ft4 = free thyroxine; IRMA = immunoradiometric assay; TSH = thyrotropin.. (From Caldwell G, Kellett HA, Gow SM. Beckett GJ, Sweeting VM, Seth J, Toft AD: A new strategy for thyroid function testing. Laneet 1: , 1119, By permission.)

11 Interpretation of TSH and FT4 Results Low Normal High (pmmol/l) 4 FT High Norm al Hyperthyroidism Subclinical hyperthyroidism T3 thyrotoxicosis Pregnancy (first trimester) Drugs (eg. Glucocorticoids, dopamine, amiodarone) Euthyroid sick syndrome T4T4 autoantibodies Thyroid hormone resistance syndrome TSH-secreting pituitary Euthyroidism Thyroid Thyroid hormone resistance syndrome TSH-secreting pitutary adenoma Subclinical (compensated) hypothyroidism Low Central hypothyroidism Central hypothyroidism Euthyroid sick syndrome (more severe, uncommon) Primary hypothyroidism TSH ( ) miu/l

12 Causes of an undetect ectable/suppressed TSH Thyrotoxicosis Transient hyperthyroxinemic state Hypopituitarism / central hypothyroidism Euthyroid patients in the first trimester of pregnancy Exophthalmic Graves disease Nodular goitre Early weeks and months following treatment of hyperthyroidism Nonthyroidal medical illness Psychiatric illness, e.g. Depressive disorders, schizophrenia Medications such as corticosteroids, dopamine Exogenous thyroxine

13 Prevalence of Thyroglobulin Autoantibody (TGAb) ) and Thyroid Peroxidase Autoantibody (TPOAb) TGAb TPOAb Graves disease 67% 87% Hashimoto s thyroiditis % % Non-organ organ specific auto-immune disease 35% 50% Normal controls 10-18% 18% 10-18% 18%

14 Assessment of Thyroid Anatomy and Structure 1. X-Ray of the thoracic inlet trachea compression and distortion, retrosternal extension 2. Ultrasound size, texture, nodules, retro-orbital orbital changes 3. Isotope scan (I 131 ) / (Tc 99M ) size, shape, position, activity, nodules 4. CT scan / MRI of orbit infiltrative ophthalmopathy 5. Percutaneous biopsy fine needle aspiration (FNA) cytology, trucut biopsy

15 Thyroid disease Medical: Hyperthyroidism (Thyrotoxicosis) Hypothyroidism Thyroiditis Surgical: Goitre Nodules Cancer

16 Common Symptoms and Signs of Hyperthyroidism Symptoms Palpitations Heat intolerance Nervousness Insomnia Breathlessness Increases bowel movements Light or absent menstrual periods Fatigue Signs Fast heart rate Trembling hands Weight loss Muscle weakness Warm moist skin Hair loss Staring gaze Enlarged thyroid gland

18 Clinical Features of Hyperthyroidism (the most common features are a in italic) General Ocular (5.3.2) Heat intolerance, sweating Weight loss despite increased appetite Fatigue Lymphadenopathy* Cardiovascular Palpitations, dyspnoea Sinus tachycardia, atrial fibrillation Systolic hypertension, collapsing pulse, flow murmurs Cardiac failure Neuromuscular Tremor, choreoathetosis Muscle weakness, proximal myopathy Periodic paralysis Myasthenia gravis* Neuropsychiatric Nervousness, agitation Depression, insomnia Emotional lability, poor concentration Psychosis Lid retraction, lid lag Stare and photophobia* Increased lacrimation and grittiness of eyes* Periorbital puffiness* Chemosis (conjunctival oedema)* Proptosis,, corneal ulceration* Ophthalmoplegia, diplopia* Papilloedema,, loss of visual acuity* Reproductive Oligo-amenorrhoea Infertility Impotence Gynaecomastia, poor concentration Brittle nails, Gastrointestinal Increased frequency and softening of bowel motions Vomiting Splenomegaly* Dermatological Pruritus Palmar erythema Ankle oedema Thinning of hair, alopecia Brittle nails, onycholysis Finger clubbing (acropachy)* Pretibial myxoedema (Figure 5.3.3) Goitre Diffuse with / without bruit* Nodular

19 Causes of Hyperthyroidism Normal / High RAIU Graves disease Toxic multinodular goitre Solitary toxic nodule Choriocarcinoma or hydatiform mole Hyperemesis gravidarum (gestational hyperthyroidism) TSH secreting pituitary adenoma Pituitary selective thyroid hormone resistance syndrome RAIU = radioactive iodine uptake Low RAIU Subacute thyroiditis Painless(silent)thyroiditis Postpartum thyroiditis Factitious hyperthyroidism Iodine-induced induced hyperthyroidism (Jod-Basedow Basedow) Struma ovarii Metastatic functioning thyroid carcinoma

20 A Case of Hyperthyroidism due to Graves Disease F/33, housewife c/o weight loss of 10 lbs in 2 months despite good appetite, heat intolerance, increased sweating, palpitation and bad temper Pulse 100/min, sweaty palm, hand tremor, stare look, diffuse goitre with bruit TSH < 0.01 miu/l, FT4 = 60.6 pmol/l, TgAb 1/400, TPOAb 1/1600, USS showed a diffuse goitre

21 Thyroid Eye Signs Lid retraction, lid lag (sympathetic overtone) Periorbital puffiness Chemosis Proptosis,, corneal ulceration Ophthalmoplegia Optic nerve compression

23 Selection of Antithyroid Treatment for Common Forms of Hyperthyroidism Antithyroid drugs (thionamide) ) (ATD) Radioiodine (RAI) Subtotal thyroidectomy (SX) Strongly indicated Thyrotoxic crises or severe Preparation for RAI/SX Pregnancy Young Young Graves disease Relapse Relapse after SX Thyrotoxic heart disease after stabilization Hyperthyroidism with concomitant disease or complication Large Large and/or nodular goitre with pressure symptoms Rapidly Rapidly growing goitre with suspicion of cancer Not recommended As As long-term treatment in toxic nodules or toxic multinodular goitre For For relapse of Graves disease after first course of ATD or after SX Large Large vascular and/or nodular goitre Poor Poor drug compliance young patients (arbitrary limit < 20 years) Large Large compressing and/or retrosternal goitre Unstable Unstable significant Graves ophthalmopathy Relapse Relapse after first operation Patients Patients relying on their voice for their profession Contraindicated Known Known fatal allergy to thionamides (blood dyscrasia, hepatotoxicity, see text) Pregnancy Thyrotoxic crises Thyrotoxicosis not yet controlled by drugs

24 Example of ATD Regimen: One course of ATD varies from 9 months to 2 years, average months. e.g. medications by titration method: (carbimazole [CBZ] 10mg = propylthiouracil [PTU] 100mg) Dosage CBZ mg tds / 15 mg bd Duration/FU 4 6 wks 10mg bd 8 10 wks 15mg OD wks 10 mg OD wks 5 mg OD wks

25 Side Effects of ATD Side effects Action Skin rash, pruritus, arthralgias Agranulocytosis Cholestatic hepatitis Try other alternative ATD Stop and never ATD again, may need admission Stop and evaluate,? Try other ATD It s a good practice to mention and warn patients about these possible side effects (severs toxic reaction is extremely rare from our own experiences) when first starting ATD. Any doubt, check CBP, LFT PTU to be preferred during pregnancy

26 WBC & Thyrotoxicosis Graves thyrotoxicosis may have low WBC & platelet at presentation 0.5 to 1.0 % may develop agranul nulocytosis after ATD, usually abrupt presentation,, routine CBP surveillance not indicated Routine warning to patients Recovery within 1 week, may be shortened with G-CSFG

27 Liver Derangement & Thyrotoxicosis Related directly to the state of thyrotoxicosis mild ALT, Alk PO 4 (bone) Thyrotoxic heart disease with CHF and congested liver Idiosyncratic reaction to thionamides antithyroid medications Aetiologically related to the underlying Graves disease autoimmune hepatitis, primary biliary cirrhosis

28 Radioiodine Therapy- Facts (1) Nearly for all causes of hyperthyroidism Safely be given to patients of all age gp but is less often given to children <10 yrs old Contraindicated in pregnancy and while breast feeding No increased risk of thyroid cancer, leukaemia,, solid tumours, teratogenicity and chromosome damage

29 Radioiodine Therapy- Facts (2) The recommended strategy is to give an activity sufficient to render the patient rapidly euthyroid and maintain that state or achieve no more than a low rate of hypothyroidism in subsequent years A range of activity ( MBq) ) is suggested depending on the clinical state ATD may be given before or after RAI (or both) if necessary

30 Radioiodine Therapy- Facts (3) Administration of RAI must conform to regulations and definitions as stated by government board Full written information should be given to the patient and written consent obtained A structured FU should be used ensuring regular measurement of TSH and FT4

31 RAI-Indications Indications Toxic nodular goitre - treatment of choice Post-thyroidectomy thyroidectomy Graves disease first-line relapse compliance concommitant clinical or social factors

32 Contraindications to RAI Pregnancy and breast feeding Situations where it is clear that the safety of other persons cannot be guaranteed Known allergy to iodine Relative - eg urinary incontinence without a catheter, significant retrosternal goitre

33 RAI - other factors f to consider Patient age, gender and response to ATD Causes and severity of hyperthyroidism Patient and doctor preference and access to RAI Safety Cost

34 Side Effects of RAI No documented allergic reactions to RAI Radiation gastritis Radiation thyroiditis anterior neck pain transient exacerbation of thyrotoxicosis? increased compressive symtoms Subsequent development or worsening of infiltrative ophthalmopathy

35 Common Symptoms and Signs of Hypothyroidism Symptoms Fatigue Feeling slow or tired Cold intolerance Muscle aching and cramps Memory loss Depression Constipation Heavy menstrual flow Decreased libido, infertility Signs Slow heart rate Dry, coarse, yellowish skin Weight gain Facial and hand puffiness Husky voice Thinning hair In children, short stature Enlarged thyroid gland

36 Clinical Features of Hypothyroidism (the most common features are in italic) General Tiredness Weight gain Cold intolerance Hypothermia Goitre Hyperlipidaemia Cardiovascular Bradycardia Angina Heart failure Hypertension Pericardial effusions Respiratory Dyspnoea Reduced inspiratory effort Pleural effusions Neuromuscular Aches and pains Myalgia and muscle cramp Joint stiffness Paresthesias Carpel tunnel syndrome Hoarseness Deafness Cerebellar ataxia Myotonia Delayed relaxation of reflexes Neuropsychiatric Lethargy Fatiability Sleepiness Delirium Dementia Depression Psychosis ( myxoedema madness ) Haematological Iron deficiency anaemia Macrocytic anaemia Pernicious anaemia Normochromic normocytic anaemia Dermatological Dry cool skin Brittle nails Coarse hair Alopecia Oedema Myxoedema (especially facial and periorbital tissres) Vitiligo Erythema ab igne Reproductive Infertility Impotence Menorrhagia Galactorrhoea and hyperprolactinaemia Gastrointestinal Constipation Ileus,, rarely toxic megacolon Abdominal distension Developmental Growth retardation Mental retardation Short stature Delayed puberty

37 What Causes Hypothyroidism One common cause of thyroid gland failure is Hashimoto s thyroiditis,, a painless disease of the immune system that runs in families. Thyroid surgery or radioactive iodine treatment may cause hypothyroidism One out of every infants is born with hypothyroidism. If the problem is not corrected promptly, the child will become mentally and physically retarded

38 Iodine Deficiency Disorders About 100 million people around the world (usually inland mountainous area) don t t get enough iodine in their diets. Iodine is a chemical which the thyroid uses to produce its hormones Adding iodine to salt as a national policy could solve the problem for endemic iodine deficiency area

39 Causes of Hypothyroidism Primary hypothyroidism Thyroid agenesis / dysgenesis Thyroid gland destruction Hashimoto s thyroiditis Post-thyroidectomy thyroidectomy Post-radioiodine radioiodine/neck irradiation Post-subacute subacute/silent thyroiditis Thyroid gland atrophy Atrophic thyroiditis/primary agoitrous Disorders of thyroid hormone synthesis Iodine deficiency Drugs (thionamides,, lithium, iodide, amiodarone) Dyshormonogenesis (inherited enzyme deficiencies) Secondary hypothyroidism (pituitary) Pituitary tumour (primary or metastatic) Autoimmune hypophysitis Pituitary irradiation or surgery Tertiary hypothyroidism (hypothalamic) Hypothalamic tumour or destruction Generalized or peripheral thyroid hormone resistance

40 A Case of Hypothyroidism due to Hashimoto s Thyroiditis F/16, student c/o weight gain of 10 lbs in 3 months, cold intolerance, feeling slow and tired, drowsy during the day, heavy menstrual flow Pulse 60/min, dry, cold hand with yellowish skin, puffy face, small diffuse firm goitre TSH = 85 miu/l, FT4 = 3.2 pmol/l, TgAb 1/100, TPOAb 1/25,600, USS showed a diffuse goitre

41 Treatment Daily L-thyroxineL replacement Titrate according to TSH (0.10 mg daily for average adult, or mg/kg daily), allow >6 weeks before monitor Caution in patients with IHD or elderly, start at low dose If suspect adrenal insufficiency or hypopituitarism,, must replace steroids before thyroxine

42 Thyroid enlargement (Goitre) Diffuse or nodular Single nodule or multinodular Cystic or solid Benign or malignant Any pressure effects Simple euthyroid Hyperthyroid Hypothyroid?Autoimmunity Neck palpation Thyroid scintiscan Ultrasound FNA Examination TFTs TGAb & TPOAb

43 Etiology of Simple Goiter 1. Iodine deficiency 2. Iodine excess 3. Goitrogenic agents a. Drugs b. Food stuffs 4. Dyshormonogenesis 5. Autoimmunizing thyroiditis 6. Ionizing radiation

44 Nomenclature of thyroiditis according to the American Thyroid Association (WERNER 1969) American Thyroid Association Synonyms Subacute or acute nonsuppurative thyroiditis Chronic lymphocytic thyroiditis Chronic invasive fibrous thyroiditis Acute suppurative thyroiditis Granulomatous thyroiditis Giant cell thyroiditis De Quervain s thyroiditis Hashimolo s thyroiditis Struma lymphomatosa Autoimmune thyroiditis Riedel s thyroiditis Chronic nonsuppurative thyroiditis due to specific infection (tuberculosis, syphilis)

45 De Quervain s thyroiditis Spontaneously remitting inflammatory disease of the thyroid gland Believed to be viral in aetiology Incidence : not an uncommon disease, Woolner et al collected 162 cases over 5 years, approximate one-eighth eighth the incidence of Graves disease and 50 times more frequently than Riedel s thyroiditis

46 De Quervain s thyroiditis Clinical features: Pain and tenderness in thyroid region Malaise, fatigue with fever (PUO) Typically gradual onset over 1 to 2 weeks, continues with fluctuating intensity for 3 to 6 weeks

47 De Quervain s thyroiditis Approximately one half of the patient present in first week with symptoms of thyrotoxicosis Hoffman HS (US) and Harefuah (Israel) reported 2 cases presented as PUO similar to our local experiences Demonstrated association with HLA-B35 and B67 by Ohsako (Japan) in

48 De Quervain s thyroiditis Diagnosis : clinical, with striking elevation in ESR, mild leucocytosis and high serum T4, T3 level Low thyroidal RAIU Birchall, Chow and Metreweli in demonstrated the ultrasonic features and striking volume change after treatment of 2 cases of De Quervain s thyroiditis in HK

49 De Quervain s thyroiditis Treatment : some patients do not need treatment, most of them need NSAID as analgesic, if this fails : 1 short course steroid for weeks Prognosis : 90% with complete and spontaneous recovery and return to normal thyroid function. Litaka (Japan) evaluated 3344 patients, at least recur in 2% of patients and exhibited relatively mild clinical manifestation

50 Other topics of interest Pregnancy related thyroid disorders Hyper & Hypothyroidism Postpartum thyroiditis Thyrotoxic heart disease Thyrotoxic periodic paralysis Thyroid Disorders in the Elderly

Effect of thyroid hormones of metabolism Thyroid Diseases

Effect of thyroid hormones of metabolism Thyroid Diseases Medical Perspective Aspects That Will Be Addressed Regulation of thyroid hormone secretion Basic physiology Hyperthyroidism Hypothyroidism Thyroiditis