Hyperthyroidism&

Hypothyroidism

TSH: 7,1 mU/L (?)

Overview1. Thyroid physiology

2. Hypothyroidism

3. Hyperthyroidism

4. Tumors

5. Case History 1-6

• Failure of the gland to develop causescongenital hypothyroidism.

• Under- or over-migration of the thyroid cancause a lingual or retrosternal thyroidrespectively.

• Failure of thyroglossal duct to atrophy canlead to a thyroglossal cyst.

The Thyroid gland and its downward migration

Regulation of Thyroid hormone synthesis

TRH: thyrotropin-releasing hormoneTSH:Thyroid-stimulating hormoneTSH-R: TSH receptorT4: ThyroxineT3: TriiodothyronineTg: ThyroglobulinTPO: Thyroid peroxidaseMIT: monoiodotyrosineDIT: diiodotyrosineNIS: sodium iodide symporter

Structures of Thyroid Hormones

TSH: 0.34–4.25 mU/L

free T4: 9–16 pmol/L

free T3: 3.7–6.5 pmol/L

Circulating Thyroid Hormones

• Thyroid hormones are almost entirelybound to serum proteins (in order of decreasing affinity):° Thyroxine-binding globulin (TBG)° Thyroxine-binding pre-albumin (TBPA)° Albumin• The unbound fraction is tiny, yetcritical – only free thyroid hormone enters cells and is biologically active:° Free T4 (fT4) ∼0.015% of total T4° Free T3 (fT3) ∼0.33% of total T3

° Circulating half-life of T3, ∼1–3days – needs to be prescribed severaltimes a day if used to achieve steadylevels° Circulating half-life of T4, ∼5–7days – can be prescribed as single dailydose° Both fT4 and fT3 are measured byimmunoassay• T3 is more potent than T4 (∼2–10-folddepending on response monitored)

Mechanism of Thyroid Hormone Receptor Action

Iodine and Selenium2 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 150–250 ug/d for adults, 90–120 ug/d for children, and 250 ug/d for pregnant and lactating women.

Recommended intake of selenium is about 100ug/d.

Worldwide Iodine Nutrition

Tests to determine the etiologyof thyroid dysfunction

1.Thyroid function tests (TSH, fT3, fT4)2.TPO, TG, TSH antibodies3. 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

Interpretation of Thyroid Function tests

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 – hypoplasiaor aplasia

Secondary/Tertiary hypothyroidism: pituitary or hypothalamic disease (assess other hormone axes)

Causes of hypothyroidism

Symptoms and signs of hypothyroidism

• Weight gain

• Cold intolerance, particularly at extremities

• Fatigue, lethargy

• Depression

• Coarse skin and puffy appearance

• Dry hair

• Hoarse voice

• Constipation

• Menstrual irregularities (altered luteinizing

hormone/follicle-stimulating hormone secretion)

• Possible goitre

• ‘Slow’ reflexes, muscles contract normally, but relax slowly

• Generalized muscle weakness and paraesthesia

• Bradycardia (with reduced cardiac output)

• Cardiomegaly (with possible pericardial effusion)

• Possible carpal tunnel syndrome

• Loss of outer third of eyebrows (reasonunclear)

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)

Treatment - Clinical Hypothyroidism

Adult patients under 60 without evidence of heart disease may be started on 50–100 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 12.5- or 25-ug increments.

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.

Myxoedema comavery 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 oraland intravenous T4 and T3 have beenadvocated with no clear consensus (single IV bolus of 500ug levothyroxine + 50-100ug daily)• Even with treatment, mortality is high.

Hyperthyroidism

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),

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

Treatment of Hyperthyroidism1. 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 12–18 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-131- same preparation as surgery (euthyroidism first)

Thyroid malignancy

Approach to diagnosing Thyroid malignancy

Case History1-6

#1A 45-year-old woman attended her doctor having felt ‘not quite right’ for the last 6 months. Shewas tired and her hair had been falling out. She had noticed her periods being heavy andrather erratic and wondered whether she was entering the menopause. She had put on 5 kgduring 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), TSH23.4 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?

#2A 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. Colleagueshad 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 providedproof: TSH less than 0.01 mU/L, fT4 82.7 pmol/L (∼6.5 ng/dL), fT3 14.2 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?

#3A 45-year-old woman attends her family doctor because of pain in her right eye, which hasbeen weepy, sore, red and protuberant for the last 2 weeks. She also has pain behind her lefteye which otherwise appears normal. She smokes 10 cigarettes/day. The doctor notices a scaron 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?

#4An 81-year-old man was referred by the cardiologist with TSH less than 0.14 mU/L, fT432.4 pmol/L (∼2.5 ng/dL), and fT3 6.2 pmol/L (0.4 ng/dL). He has been taking amiodarone for thelast 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.

#5A 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 herneck that moved on swallowing. There was no palpable lymphadenopathy. There wasno family history of cancer. TSH 1.34 mU/L, fT4 13.4 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?

#6A 48-year-old man presented to his family doctor with a swelling at the base of the neck thathad come on over the last 3 months. He had had a hoarse voice for the last 2 weeks. TFTswere normal.

1. Is this presentation concerning?2. What additional features might be present on examination of the neck?