Hyperthyroidism & Hypothyroidism

Transcription

1 Hyperthyroidism & Hypothyroidism

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3 TSH: 7,1 mu/l (?)

4 Overview 1. Thyroid physiology 2. Hypothyroidism 3. Hyperthyroidism 4. Tumors 5. Case History 1-6

5 The Thyroid gland and its downward migration Failure of the gland to develop causes congenital hypothyroidism. Under- or over-migration of the thyroid can cause a lingual or retrosternal thyroid respectively. Failure of thyroglossal duct to atrophy can lead to a thyroglossal cyst.

6 Regulation of Thyroid hormone synthesis TRH: thyrotropin-releasing hormone TSH:Thyroid-stimulating hormone TSH-R: TSH receptor T4: Thyroxine T3: Triiodothyronine Tg: Thyroglobulin TPO: Thyroid peroxidase MIT: monoiodotyrosine DIT: diiodotyrosine NIS: sodium iodide symporter

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8 Structures of Thyroid Hormones

9 TSH: mu/l free T4: 9 16 pmol/l free T3: pmol/l

10 Circulating Thyroid Hormones Thyroid hormones are almost entirely Circulating half-life of T3, 1 3 bound to serum proteins (in order of decreasing affinity): days needs to be prescribed several Thyroxine-binding globulin (TBG) levels Thyroxine-binding pre-albumin (TBPA) Circulating half-life of T4, 5 7 Albumin days can be prescribed as single daily The unbound fraction is tiny, yet dose critical only free thyroid hormone enters cells and is biologically active: Both ft4 and ft3 are measured by Free T4 (ft4) 0.015% of total T4 Free T3 (ft3) 0.33% of total T3 times a day if used to achieve steady immunoassay T3 is more potent than T4 ( 2 10-fold depending on response monitored)

11 Mechanism of Thyroid Hormone Receptor Action

12 Iodine and Selenium 2 billion people are iodine-deficient. Increased prevalence of goiter and, when deficiency is severe, hypothyroidism and cretinism. Cretinism is characterized by mental and growth retardation. Concomitant selenium deficiency may also contribute to the neurologic manifestations of cretinism. Iodine supplementation of salt, bread, and other food substances. Oversupply of iodine is associated with an increased incidence of autoimmune thyroid disease. Recommended average daily intake of iodine is ug/d for adults, ug/d for children, and 250 ug/d for pregnant and lactating women. Recommended intake of selenium is about 100ug/d.

13 Worldwide Iodine Nutrition

14 Tests to determine the etiology of thyroid dysfunction 1.Thyroid function tests (TSH, ft3, ft4) 2.TPO, TG, TSH antibodies 3. Thyroid ultrasound - detection of nodules and cysts >3mm - Fine Needle Aspiration Biopsy (FNAB) 4. Radioiodine uptake - hot nodules: increased tracer uptake, almost never malignant - cold nodules: decreased uptake, 5-10% malignant

15 Interpretation of Thyroid Function tests

16 Hypothyroidism

17 Causes of hypothyroidism Primary hypothyroidism Goiter Autoimmune Hashimoto thyroiditis Iodine deficiency Drugs (e.g. lithium) Riedel thyroiditis Congenital hypothyroidism No Goiter Autoimmune atrophic thyroiditis Post-radioiodine ablation or surgery Post-thyroiditis (hypothyroidism is transient) Congenital hypothyroidism hypoplasia or aplasia Secondary/Tertiary hypothyroidism: pituitary or hypothalamic disease (assess other hormone axes)

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19 Symptoms and signs of hypothyroidism Weight gain Possible goitre Cold intolerance, particularly at extremities Fatigue, lethargy Depression Slow reflexes, muscles contract normally, but relax slowly Generalized muscle weakness and paraesthesia Coarse skin and puffy appearance Dry hair Bradycardia (with reduced cardiac output) Hoarse voice Cardiomegaly (with possible pericardial effusion) Constipation Possible carpal tunnel syndrome Menstrual irregularities (altered luteinizing hormone/follicle-stimulating hormone secretion) Loss of outer third of eyebrows (reason unclear)

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23 Hashimoto s Thyroiditis First disease to be recognized as an autoimmune disease (1912). Atrophy of the thyroid follicles accompanied by oxyphil metaplasia, absence of colloid, and mild to moderate fibrosis. 4 per 1000 women - 1 per 1000 men, mean age of diagnosis is 60 Chronic lymphocytic thyroiditis. Cell destruction is primarily mediated by the CD8+ cytotoxic T cells. Thyroid peroxidase (TPO) and/or thyroglobulin (Tg) and TSH-R-blocking antibodies. HLA-DR and CTLA-4 polymorphisms account for approximately half of the genetic susceptibility to autoimmune hypothyroidism. Chronic exposure to high-iodine diet. (Japanese)

24 Treatment - Clinical Hypothyroidism Adult patients under 60 without evidence of heart disease may be started on ug levothyroxine (T4) daily. The dose is adjusted on the basis of TSH levels, with the goal of treatment being a normal TSH, ideally in the lower half of the reference range. Check TSH after 2 months of treatment. Once stable, annual check. Clinical response is slow to appear. Adjustment of levothyroxine dosage is made in or 25-ug increments.

25 Treatment - Subclinical Hypothyroidism No apparent clinical features of hypothyroidism. No routine treatment when TSH levels are below 10 mu/l. Risk to progress to overt hypothyroidism, particularly when the TSH level is elevated and TPO antibodies are present. Starting with a low dose of levothyroxine (25 50 ug/d) with the goal of normalizing TSH. Treat before/during pregnancy and with TPO antibodies.

26 Myxoedema coma very severe hypothyroidism Features Diminished mental function confusion coma Usually in the elderly Hypothermia Low cardiac output/cardiac failure Pericardial effusion Hyponatraemia and hypoglycaemia Hypoventilation Treatment Identify any precipitating cause (e.g.infection) Gradual re-warming Supportive ITU management (protect airway in coma, oxygen, broad-spectrum antibiotics, cardiovascular monitoring, glucose, monitor urine output) Take blood for TFTs Treat with hydrocortisone until hypoadrenalism excluded Thyroid hormone replacement both oral and intravenous T4 and T3 have been advocated with no clear consensus (single IV bolus of 500ug levothyroxine ug daily) Even with treatment, mortality is high.

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28 Hyperthyroidism

29 Hyperthyroidism Thyroid overactivity causing increased circulating thyroid hormones - Thyrotoxicosis Viral infection or overdose of oral thyroxine will cause transient thyrotoxicosis, but this is not hyperthyroidism. Most commonly hyperthyroidism has an autoimmune origin (Graves disease) Other causes: autonomous thyroid nodule, amiodarone, TSH secreting pituitary adenoma, pregnancy (hcg signalling via TSH receptor),

30 Graves disease Thyroid-stimulating IgG antibodies that activate the TSH receptor on the follicular cell surface. 10x women than men. Between 20 and 50 years of age. Genetic factors: polymorphisms in HLA-DR, CTLA-4, CD25, PTPN22 Environmental factors: high iodine uptake, stress, smoking

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36 Treatment of Hyperthyroidism 1. Antithyroid Drugs: - high dose of drug can be started (e.g. thiamazole 60 mg/day) and titrated down according to falling ft4 levels on TFTs. - treat for months and then to withdraw treatment to test for spontaneous remission - Block and replace regime - Can cause agranulocytosis!! 2. Surgery: - Subtotal or total thyroidectomy - Operating on an acutely overactive gland risks thyroid storm. - can damage the recurrent laryngeal nerve - hypoparathyroidism 3.Radioiodine: - Iodine same preparation as surgery (euthyroidism first)

37 Thyroid malignancy

38 Approach to diagnosing Thyroid malignancy

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40 Case History 1-6

41 #1 A 45-year-old woman attended her doctor having felt not quite right for the last 6 months. She was tired and her hair had been falling out. She had noticed her periods being heavy and rather erratic and wondered whether she was entering the menopause. She had put on 5 kg during the last 6 months. The doctor did some blood tests: Na+ 134 mmol/l (134 meq/l), K+ 3.8 mmol/l (3.8 meq/l), urea 4.2 mmol/l ( 11.8 mg/dl), creatinine 95 μmol/l ( 1.1 mg/dl), TSH 23.4 mu/l, ft4 6.7 pmol/l ( 0.5 ng/dl), Hb 112 g/l, gonadotrophins were normal. 1. What is the endocrine diagnosis and why? 2. What is the treatment? 3. What is the potential significance of the haemoglobin level?

42 #2 A 32-year-old man attended his doctor having lost 10 kg in weight and with poor sleep. He felt on edge and had had difficulty concentrating at work. He smokes five cigarettes/day. Colleagues had commented on his staring appearance. The doctor completes the history and examination and takes a blood test. He knew the likely diagnosis beforehand, however, the results provided proof: TSH less than 0.01 mu/l, ft pmol/l ( 6.5 ng/dl), ft pmol/l ( 0.9 ng/dl). 1. What is the biochemical diagnosis and why? 2. What features of the examination could have implied the diagnosis without the blood test? 3. Describe a suitable management plan? 4. Once the thyrotoxicosis has settled, what definitive treatment of hyperthyroidism might be ill-advised at present?

43 #3 A 45-year-old woman attends her family doctor because of pain in her right eye, which has been weepy, sore, red and protuberant for the last 2 weeks. She also has pain behind her left eye which otherwise appears normal. She smokes 10 cigarettes/day. The doctor notices a scar on her neck. 1. Why is the scar of interest? 2. What is significant about the pain behind the left eye? 3. What investigations and management should be considered?

44 #4 An 81-year-old man was referred by the cardiologist with TSH less than 0.14 mu/l, ft pmol/l ( 2.5 ng/dl), and ft3 6.2 pmol/l (0.4 ng/dl). He has been taking amiodarone for the last 6 months for supraventricular arrhythmia. On questioning he has shortness of breath. 1. Give three possible causes of the mild thyrotoxicosis. 2. If considered to be hyperthyroidism, what treatment would restore euthyroidism? 3. Give one drug-related reason why the patient might be short of breath.

45 #5 A 55-year-old woman who had lived in the UK all her life attended her family doctor because of a sense of fullness in her neck. It had been present for at least 5 years and had not changed in nature but was perhaps minimally larger. The patient was worried. The doctor examined her and discovered a non-symmetrical firm mass either side of and close to the midline at the base of her neck that moved on swallowing. There was no palpable lymphadenopathy. There was no family history of cancer. TSH 1.34 mu/l, ft pmol/l, ft3 4.7 pmol/l ( 0.3 ng/dl). 1. What is the likely diagnosis? 2. What further investigation would help provide complete reassurance? 3. What follow-up might be suggested?

46 #6 A 48-year-old man presented to his family doctor with a swelling at the base of the neck that had come on over the last 3 months. He had had a hoarse voice for the last 2 weeks. TFTs were normal. 1. Is this presentation concerning? 2. What additional features might be present on examination of the neck?