HYPERTHYROIDISM

1. HYPERTHYROIDISM (thyroid over activity, thyrotoxicosis)

2. It is common, affecting perhaps 2-5% of all females at some time and with a sex ratio of 5 : 1. • Most often between ages 20 and 40 years. • Nearly all cases (> 99%) are caused by intrinsic thyroid disease; a pituitary cause is extremely rare .

3. Causes of hyperthyroidism Common • Graves' disease (autoimmune) • Toxic multinodular goitre • Solitary toxic nodule/adenoma Uncommon • Acute thyroiditis • viral (e.g. de Quervain's) • autoimmune • post-irradiation • postpartum

4. Gestational thyrotoxicosis (HCG stimulated) • Neonatal thyrotoxicosis (maternal thyroid antibodies) • Exogenous iodine • Drugs - amiodarone • Thyrotoxicosis factitia (secret T4 consumption) Rare • TSH-secreting pituitary tumours • Metastatic differentiated thyroid carcinoma • HCG-producing tumours • Hyperfunctioning ovarian teratoma (struma ovarii)

5. Graves' disease: • This is the most common cause of hyperthyroidism and is due to TSH receptor antibodies (IgG) that bind to the thyroid TSH receptor stimulating thyroid hormone production, behaving like TSH. • These TSH receptor antibodies can be measured in serum. • 50% concordance is seen amongst monozygotic twins with a 5% concordance rate in dizygotic twins. • the initiating event in the pathogenesis may be an infection ' in a genetically susceptible individual,(as Yersiniaenterocolitica ,Escherichia coli and other Gram-negative organisms contain TSH binding sites), but the precise initiating mechanisms remain unproven in most cases.

6. Thyroid eye disease is commen in Graves' disease. • Graves' dermopathy, are very rare. • Rarely lymphadenopathy and splenomegaly may occur. • Graves' disease is also associated with other autoimmune disorders such as pernicious anaemia, vitiligo and myasthenia gravis. • The natural history is one of fluctuation, with alternating relapse and remission; perhaps only 40% of subjects have a single episode. • Many patients eventually become hypothyroid.

7. Grave’s Disease Proptosis and lid lag.

8. Pretibial Myxedema Waxy infiltrative plaques and edema,consistent with infiltrative dermopathy of Grave’s disease.

9. Toxic multinodular goitre: • This commonly occurs in older women. • Antithyroid drugs are rarely successful in inducing a remission - although they can control the hyperthyroidism. Toxic solitary adenoma/nodule (Plummer's disease): • This is the cause of about 5% of cases of hyperthyroidism. • It does not usually remit after a course of antithyroid drugs.

10. De Quervain's thyroiditis : • This is transient hyperthyroidism from an acute inflammatory process, probably viral in origin. • In addition to toxicosis, there is usually fever, malaise and pain in the neck with tachycardia and local thyroid tenderness. • Thyroid function tests show initial hyperthyroidism, high erythrocyte sedimentation rate (ESR), and thyroid uptake scans show suppression of uptake in the acute phase. • Transient Hypothyroidism, usually may follow after a few weeks. • Treatment of the acute phase is with aspirin, using short-term prednisolone in severely symptomatic cases.

11. Clinical Manifestations: • The clinical presentation depends on the severity of thyrotoxicosis, the duration of disease, individual susceptibility to excess thyroid hormone, and the patient's age. • Symptoms •  Hyperactivity, nervousness, and irritability, ultimately leading to a sense of easy fatigability and weakness. • Insomnia and impaired concentration are common •   Heat intolerance and sweating •   Palpitations  •   Weight loss with increased appetite due to the increased metabolic rate. •   Diarrhea • Polyuria • Oligomenorrhea, loss of libido

12. N.B. Apathetic thyrotoxicosis It occures in some elderly patients ,the clinical presentation is more like hypothyroidism, with very few signs and so, high degree of clinical suspicion is essential. Signs •   Tachycardia; atrial fibrillation in the elderly. The high cardiac output produces a bounding pulse, widened pulse pressure, and an aortic systolic murmur. •   Fine tremor •   Goiter :In Graves' disease the thyroid is usually diffusely enlarged to two–three times its normal size. The consistency is firm, but less so than in MNG. There may be a thrill or bruit due to the increased vascularity of the gland and the hyperdynamic circulation.

13. Warm, moist skin,palmarerythema, onycholysis, and, less commonly, urticaria, and diffuse hyperpigmentation may be evident. • Hair texture may become fine, and a diffuse alopecia occurs in up to 40% of patients. •   Muscle weakness, proximal myopathy •   Lid retraction or lag resulting from sympathetic overactivity • Gynecomastia

14. Differential diagnosis : • Hyperthyroidism is often clinically obvious but treatment should never be instituted without biochemical confirmation. • Differentiation of the mild case from anxiety states may be difficult; useful positive clinical markers are eye signs, a diffuse goitre , proximal myopathy , wasting and warm sweaty peripheries.

15. Investigations : • Serum TSH is suppressed in hyperthyroidism (< 0.05 mU/L), except in cases secondary to TSH hypersecretion. • Raised free T4 or T3; T4 is almost always raised but T3 is more sensitive as there are occasional cases of isolated 'T3toxicosis'. • TPO and thyroglobulin antibodies are present in most cases of Graves' disease. • TSH receptor antibodies are not measured routinely, but are commonly present: thyroid-stimulating immunoglobin (TSI) 80% positive, TSH-binding inhibitory immunoglobin (TBII) 60-90% in Graves' disease .

16. Treatment: • Three possibilities are available: antithyroid drugs, radioiodine and surgery. • Antithyroid drugs • The main antithyroid drugs are the thionamides, such as propylthiouracil, carbimazole, and the active metabolite of the latter, methimazole. • All inhibit the function of TPO(thyroid peroxidase), reducing oxidation and organification of iodide. These drugs also reduce thyroid antibody levels by mechanisms that remain unclear, and they appear to enhance rates of remission. • Propylthiouracil inhibits deiodination of T4 to T3. However, this effect is of minor benefit, except in the most severe thyrotoxicosis, and is offset by the much shorter half-life of this drug (90 min) compared to methimazole (6 h).

17. There are many variations of antithyroid drug regimens: • The initial dose of carbimazole or methimazole is usually 10–20 mg every 8 or 12 h, but once-daily dosing is possible after euthyroidism is restored. • Propylthiouracil is given at a dose of 100–200 mg every 6–8 h, and divided doses are usually given throughout the course. • The starting dose of antithyroid drugs can be gradually reduced (titration regimen) as thyrotoxicosis improves.

18. The usual daily maintenance doses of antithyroid drugs in the titration regimen are 2.5–10 mg of carbimazole or methimazole and 50–100 mg of propylthiouracil. • Propranolol (20–40 mg every 6 h) or longer-acting beta blockers such as atenolol, may be helpful to control adrenergic symptoms, especially in the early stages before antithyroid drugs take effect. • The need for anticoagulation with oral anticoagulant should be considered in all patients with atrial fibrillation. • If digoxin is used, increased doses are often needed in the thyrotoxic state.

19. Gradual dose titration 1. Review after 4-6 weeks and reduce dose of carbimazole depending on clinical state and T4/T3 levels. TSH levels may remain suppressed for several months and are unhelpful at this stage. 2. When clinically and biochemically euthyroid, stop beta-blockers. 3. Review after 2-3 months and, if controlled, reduce carbimazole. 4. Gradually reduce dose to 5 mg daily over 6-24 months if hyperthyroidism remains controlled. 5. When the patient is euthyroid on 5 mg daily carbimazole, discontinue.

20. Relapse: About 50% of patients will relapse after a course of carbimazole or propylthiouracil, mostly within the following 2 years but occasionally much later. • Long-term antithyroid therapy is then used or surgery or radiotherapy is considered . • patients (10%) with hyperthyroidism have a large single or multinodular goitres are unlikely to remit after a course of antithyroid drugs. • Severe biochemical hyperthyroidism is also less likely to remain in remission.

21. Side-effect of antithyroid drugs: • The major side-effect is agranulocytosis that occurs in approximately 1 in 1000 patients usually within 3 months of treatment. • All patients must be warned to seek immediate medical attention if they develop unexplained fever or sore throat - written information is essential. • Rashes are more frequent and usually require a change of drug. If toxicity occurs on carbimazole, propylthiouracil may be used and vice versa.

22. Radioactive iodine: • Radioiodine causes progressive destruction of thyroid cells and can be used as initial treatment or for relapses after a trial of antithyroid drugs. • There is a small risk of thyrotoxic crisis after radioiodine, which can be minimized by pretreatment with antithyroid drugs for at least a month before treatment. • Antecedent treatment with antithyroid drugs should be considered for all elderly patients or for those with cardiac problems, to deplete thyroid hormone stores before administration of radioiodine. • Carbimazole or methimazole must be stopped at least 3 days before radioiodine administration to achieve optimum iodine uptake , and not recommence until 3 days after radioiodine.

23. Propylthiouracil has a prolonged radioprotective effect and should be stopped several weeks before radioiodine is given, or a larger dose of radioiodine will be necessary. • Hyperthyroidism can persist for 2–3 months before radioiodine takes full effect so, beta -adrenergic blockers or antithyroid drugs can be used to control symptoms during this interval. • Persistent hyperthyroidism can be treated with a second dose of radioiodine, usually 6 months after the first dose.

24. Side-effect of Radioactive iodine: • Early discomfort in the neck and immediate worsening of hyperthyroidism are sometimes seen • The risk of hypothyroidism after radioiodine depends on the dosage but is at least 10–20% in the first year and 5% per year there after. • Pregnancy and breast feeding are absolute contraindications to radioiodine treatment, but patients can conceive safely 6 months after treatment.

25. Exacerbation of ophthalmopathy can be avoided by the use of prednisone, 40 mg/d, at the time of radioiodine treatment, tapered over 2–3 months. • The overall risk of cancer after radioiodine treatment in adults is not increased.

26. Surgery: • Subtotal or near-total thyroidectomyis an option for patients who relapse after antithyroid drugs and prefer this treatment to radioiodine. • Some experts recommend surgery in young individuals, particularly when the goiter is very large. • Conventional practice is to stop the antithyroid drug 10-14 days before operation and to give potassium iodide (60 mg three times daily), which reduces the vascularity of the gland.

27. Complications of the operation : • Early postoperative bleeding causing tracheal compression and asphyxia is a rare emergency requiring immediate removal of all clips/sutures to allow escape of the blood/haematoma. • Laryngeal nerve palsy occurs in 1%. Vocal chord movement should be checked preoperatively. Mild hoarseness is more common and thyroidectomy is best avoided in professional singers! • Transient hypocalcaemia occurs in up to 10% but with permanent hypoparathyroidism in fewer than 1%. • Recurrent hyperthyroidism occurs in 1-3% within 1 year, then 1% per year.

28. Hypothyroidism occurs in about 10% of patients within 1 year, and this percentage increases with time. It is likeliest if TPO antibodies are positive. Indications for either surgery or radioiodine are: • patient choice • persistent drug side-effects • poor compliance with drug therapy • recurrent hyperthyroidism after drugs. • Particular indications for surgery include: a large goitre, which is unlikely to remit after antithyroid medication.

29. Special situations in hyperthyroidism: Thyroid crisis or 'thyroid storm' • This rare condition, with a mortality of 10%, is a rapid deterioration of hyperthyroidism with hyperpyrexia, severe tachycardia and extreme restlessness. • It is usually precipitated by stress, infection, surgery in an unprepared patient, or radioiodine therapy. • Treatment is urgent. Propranolol in full doses is started immediately together with potassium iodide, antithyroid drugs, corticosteroids (which suppress many of the manifestations of hyperthyroidism) and full supportive measures.

30. Hyperthyroidism in pregnancy and neonatal life : • Maternal hyperthyroidism during pregnancy is uncommon and usually mild. • Diagnosis can be difficult because of misleading thyroid function tests, although TSH is largely reliable. • The pathogenesis is almost always Graves' disease. • Thyroid-stimulating immunoglobulin (TSI) crosses the placenta to stimulate the fetal thyroid. • Carbimazole also crosses the placenta, but T4 does so poorly . • The smallest dose of carbimazole necessary is used and the fetus must be monitored.

31. Fetal heart rate provides a direct biological assay of fetal thyroid status, and monitoring should be performed at least monthly. Rates above 160 per minute are strongly suggestive of fetal hyperthyroidism, and maternal treatment with carbimazole and/or propranolol may be used. • The paediatrician should be informed and the infant checked immediately after birth – over treatment with carbimazole can cause fetal goitre. • Breast-feeding while on usual doses of carbimazole or propylthiouracil appears to be safe.

32. If necessary (high doses needed, poor patient compliance or drug side-effects), surgery can be performed, preferably in the second trimester. • Radioactive iodine is absolutely contraindicated. • Untreated neonatal hyperthyroidism is probably associated with hyperactivity in later childhood

33. Thyroid hormone resistance : • Thyroid hormone resistance is an inherited condition caused by an abnormality of the thyroid hormone receptor. • Mutations to the receptor result in the need for higher levels of thyroid hormones to achieve the same intracellular effect.

34. THYROID EYE DISEASE : • This is also known as dysthyroid eye disease or ophthalmic Graves' disease. • The ophthalmopathy of Graves' disease is due to a specific immune response that causes retro-orbital inflammation. • The precise autoantigen which leads to the immune response remains to be identified, but it appears to be an antigen in retro-orbital tissue with similar immunoreactivity to the TSH receptor

35. Swelling and oedema of the extraocular muscles lead to limitation of movement and to proptosis which is usually bilateral but can sometimes be unilateral. • Ultimately increased pressure on the optic nerve may cause optic atrophy. • Histology shows focal oedema and glycosaminoglycan deposition followed by fibrosis. • TSH receptor antibodies are almost invariably found in the serum but their role in the pathogenesis is unclear. • Ophthalmopathy is more common in smokers.

36. Clinical features: • The clinical appearances are characteristic with a wide range of severity. • A high proportion of patients with Graves' disease notice some soreness,painful watering or prominence of the eyes and the 'stare' of lid retraction . • More severe proptosis occurs in a minority of cases, and limitation and discomfort of eye movement and visual impairment due to optic nerve compression are relatively uncommon. • Proptosis and lid retraction may limit the ability to close the eyes completely so that corneal damage may occur.

37. There is periorbitaloedema and conjunctivaloedema and inflammation. • Eye manifestations do not parallel the degree of biochemical thyrotoxicosis, nor the need for antithyroid therapy, but exacerbation of eye disease is more common after radioiodine treatment (15% vs 3% on antithyroid drugs). • Only 5-10% of cases threaten sight, but the discomfort and cosmetic problems cause great patient anxiety. Investigations • If the appearances are characteristic and bilateral only TSH, T3 and free T4 are measured

38. The exophthalmos should be measured to allow progress to be monitored. • If appearances or measurements are markedly discrepant in the two eyes, other retro-orbital space-occupying lesions should be considered: MRI of the orbits will exclude other causes and show enlarged muscles and oedema. Treatment • Treatment of thyrotoxicosis will not directly result in an improvement of the ophthalmopathy, • hypothyroidism must be avoided as this may exacerbate the eye problem. • Smokers should be advised to stop.

39. Treatment of the eyes may be either local or systemic, and always requires close liaison between specialist endocrinologist and ophthalmologist: • Methylcellulose or hypromelloseeyedrops to aid lubrication and improve comfort. • sleeping uprightmay be helpful and the eyelids can be taped to ensure closure at night. • Systemic steroids (prednisolone 30-120 mg daily) to reduce inflammation if more severe symptoms are present. Pulse intravenous methylprednisolone may be more rapidly effective .

40. Irradiation of the orbits (20 Gy in divided doses) is used in severe instances. This improves inflammation and occular motility but has little effect on proptosis. • Lid surgery will protect the cornea if lids cannot be closed. • Surgical decompression of the orbit(s) is occasionally needed. • Corrective eye muscle surgery may improve diplopia due to muscle changes, but should be deferred until the situation has been stable for 6 months.