Prof. Owolabi - antithyroid.docx

**THROID HORMONE AND ANTI-THYROID AGENTS** **PREPARED BY PROF OJ OWOLABI** **INTRODUCTION** The normal adult thyroid gland weighs between 15 --25 g, it is a small butterfly --shaped gland in front of the neck, enlargement from any cause is referred to as "Goiter. The thyroid gland releases majorl...

**THROID HORMONE AND ANTI-THYROID AGENTS** **PREPARED BY PROF OJ OWOLABI** **INTRODUCTION** The normal adult thyroid gland weighs between 15 --25 g, it is a small butterfly --shaped gland in front of the neck, enlargement from any cause is referred to as "Goiter. The thyroid gland releases majorly 2 hormones namely tetraiodothyronine (thyroxine T4), triiodothyronine T3 and calcitonin. These Thyroid hormones (T4 & T3) along with the Reverse T3 which is a biologically inactive isomer of T3 is synthesized by follicular epithelial cells of the thyroid gland and it requires the availability of iodine. T4 and T3 are necessary for growth, development, regulation of energy and normal body temperature. Calcitonin the 2^nd^ hormone is needed for the regulation of calcium metabolism. A normal thyroid gland secretes T3 and T4 needed for optimal growth, development, functioning and maintenance of all body tissues. They are both critical for normal skeletal and reproductive tissues. Its effects stems from protein synthesis as well as via enhancement of the effects of growth hormones. Any deficiency early in life can result in irreversible mental retardation and dwarfism. The thyroid hormones also regulates the secretion and degradation of other hormones, catecholamine, estrogens and cortisol. Thyroid hormones regulates the resting metabolic rate of most tissues (except brain, testis and spleen), produces Inotropic and chronotropic effects on the heart, it plays a role in fetal development, especially of the brain, it regulates bone turn over and mineralization. Commonest problems associated with the thyroid gland includes: Underactivity and over activity with wide spread manifestations and often requires long term treatment. When the gland is hyperactive, the features seen are similar to sympathetic nervous system (SNS) over activity although the catecholamines levels remain normal. Its effect is most pronounced on the CNS. Some of these effects of thyroid hyperactivity similar to SNS over activity includes tremor, excessive sweating, anxiety, nervousness, lid lag and retraction. The normal thyroid gland secretes sufficient amount of the thyroid hormones (T3 and T4) to maintain normal growth and development, normal body temperature and normal energy levels. They each contain 59% and 65% of iodine respectively. Hence Iodine is an integral component of T3 and T4. The iodine here is mostly obtained from food, water or drugs ingested. Iodidie is rapidly absorbed and transmitted into the extracellular fluid pool from which the gland uses about 75µg daily for hormone secretion. The rest is excreted in the urine. The release of T4 and T3 is stimulated by thyroid stimulating hormone (TSH) via stimulation of the thyroid follicular cells, 80% of T4 is released while 20% of T3 is released. TSH release is triggered by the hypothalamus that releases thyrotropin releasing hormone that triggers the pituitary gland to release TSH which then stimulates the thyroid to release T3 and T4. TSH stimulates almost all the steps of thyroid hormone synthesis right from the uptake of iodine to the release of the hormone in the blood stream. Somatostatin on the other hand inhibits the release of TSH from the anterior pituitary. Some amounts of the hormone secreted continuously into blood, almost entirely bound to plasma proteins. Thyroxine binding globulin (60% TBG), while small % remaining free (unbound). T4 is secreted in 10-20x greater amounts than T3 whileT3 is 10x more biologically active than T4. Most of the T3 is derived from peripheral conversion of T4 by 5' monodeiodinase type 1. **Biosynthesis of thyroid hormones** The starting material is iodide, iodine in the oxidized state seen in iodized salt, food etc. Iodine most times occurs as a salt referred to as iodide. Iodide is taken up by the thyroid gland and converted via enzymes. 1\. Iodide transported into the thyroid gland is referred to as iodide trapping and this trapping can be inhibited by anions such as SCN^-^. TCO4^-^ 2\. Iodide is oxidized to iodine by thyroidal peroxidase, this step can be inhibited by thioamides (anti-thyroid agents) and by iodide itself. Iodine formed then iodinates tyrosine residues referred to as thyroglobulin molecule within the gland, to form Monoiodotyrosine MIT and diiodotyrosine DIT. This step is referred to as lodine organification. 3\. Coupling of iodotyrosines: Two molecules of DIT is combined with thyroglobulin to form L-thyroxine T4 while one molecule of MIT plus one molecule of DIT forms T3. 4\. The thyroid hormones T4 and T3 are then released from the thyroglobulin by exocytosis and proteolysis. In addition some MIT and DIT are released which are deiodinated and the iodine reused. Thyroglobulin, tyrosine and iodide are also released. Proteolysis can be blocked by high levels of iodide within the gland thus inhibiting release. Thyroglobulin contains T4 and T3 in the ratio of 5:1 hence most of the hormone released is T4. T4 is however converted peripherally to T3, hence most of the T3 seen in circulation is from the peripheral conversion of T4 by monodeiodinase. The conversion of T4 to T3 can be blocked by β blockers and corticosteroids. **Transportation** T4 and T3 in the plasma bounds irreversibly to thyroxine binding globulin (TBG) protein which transports it. However about 0.04% of T4 and 0.4% of T3 exist in the free form. The transport of T4 and T3 via TBG can be inhibited by drugs, physiologic and pathologic states. Peripheral metabolism Thyroxine can be inactivated via deamination, decarboxylation or conjugation and then excreted either as a glucoronide or sulphate though in small amount. The major pathway for metabolism of thyroxine is deiodination. Deiodination of thyroxine gives rise to T3 (3,5,3,triiodothyronine) which is about 3 or 4 times more potent than T4 thyroxine. Alternatively to a lesser extent , the product of the deiodination may be rT3, reversed T3 (3,3,5 triiodothyronine) which is metabolically inactive. The conversion of T4 to T3 can be inhibited by ipodate, β blockers corticosteroids, starvation, severe illness thus resulting in low levels of T3 and high rT3 in the serum. **Regulation of thyroid hormone** The secretion of the hormone is regulated via several mechanism 1\. Autoregulation: the gland itself auto regulates the uptake of iodide and hence synthesis by intrathyroidal mechanism independent of the thyroid stimulating hormone (TSH). This mechanism is directly linked to the level of iodine in the blood. Large amount inhibits iodide organification thus leading to inhibition of hormone synthesis and thus hypothyroidism. 2\. Thyroid-Pituitary: The thyroid-pituitary feedback also regulates synthesis. The hypothalamic cells secretes thyrotropin-releasing hormone (TRH) which stimulates the synthesis and release of TSH. TSH in turn stimulates adenylyl cyclase resulting in increased synthesis and release of T4 and T3. 3\. Abnormal thyroid stimulators: Graves disease is an example in which TSH receptor stimulating antibody is secreted also called thyroid stimulating immunoglobulin (TSI). TSI binds to TSH receptor and stimulates the gland thereby facilitating hormone secretion. **Pharmacokinetics of thyroid hormone** Absorption: T4 is well absorbed orally from the duodenum and ileum, although absorption can be interfered by food, drugs such as calcium preparations, aluminum antacids, and iron. T3 is almost completely absorbed about 95% and interference is minimal by food and drugs. Metabolism: T4 and T3 metabolism occurs via the liver and can be heightened by enzyme inducers like rifampicin, carbamazepine, phenytoin, phenobarbitone. Thus patients receiving T4 may require increased dosage to maintain clinical effectiveness. In patients with hyperthyroidism, metabolic clearance in increased and half-life decreased. The reverse is seen in hypothyroidism. **Mechanism of action:** T4 and T3 dissociates from thyroglobulin proteins (TB) and the free form enters the cell either by diffusion or active transport. Within the cell, T4 enters the nucleus and binds to specific T3 receptor proteins. This T3 receptor exist in alpha and beta form. Large number of these receptors are found in the liver, kidney, heart, lungs, skeletal muscles, pituitary and intestines. A few in the brain, spleen and testes. Upon binding the receptor, the receptors are activated leading to increased formation of RNA and subsequently protein synthesis. Protein synthesis leads to the physiologic responses seen. These receptors are nuclear receptors and T4 shows about 10 times lower affinity for it than T3. CHEMISTRY I I HO O CH~2~ CH COOH I I T4 (THYROXINE) Deiodination (Activation) I HO O CH~2~ CH COOH I I T3 (3,5,3,TRIIODOTHYRONINE) Inactivation I HO O CH~2~ CH COOH I I Reverse T3 (3,3,5,TRIIODOTHYRONINE) They are all levo-isomers. **Summary of the pharmacological effects of either high or low level of the thyroid hormone** +-----------------------+-----------------------+-----------------------+ | **SYSTEM** | **THYROTOXICOSIS/** | **HYPOTHYROIDISM | | | | (LOW)** | | | **HYPERTHYROIDISM | | | | (HIGH)** | | +=======================+=======================+=======================+ | Skin | Warm moist skin, heat | Pale, cool puffy | | | intolerance, | skin, dry and brittle | | | excessive sweating, | hair, brittle nails | | | thin hair, | | | | Periorbital | | | | dermopathy (graves) | | +-----------------------+-----------------------+-----------------------+ | Metabolic | Increased basal | Decreased basal | | | metabolic rate, | metabolic rate, | | | hyperglycemia, | | | | increased free fatty | Delayed degradation | | | | of insulin | | | Acids, increased | | | | triglycerides, | Acids, decreased | | | | triglycerides, | | | & Cholesterol, | | | | increased hormone | &Cholesterol, | | | | decreased | | | Degradation, | | | | increased drug | Hormone degradation, | | | | | | | Detoxification, | decreased drug | | | weight loss | detoxification | +-----------------------+-----------------------+-----------------------+ | Reproductive | Menstrual | Infertility, | | | irregularities | hypermenorrhea | | | | | | | Decreased fertility, | Decreased libido, | | | | impotence | | | Increased gonad | | | | steroid metabolism | Decreased gonad | | | | steroid metabolism | +-----------------------+-----------------------+-----------------------+ | Haematopoietic | Increased | Decreased | | | erythropoiesis | erythropoiesis | | | | | | | Anaemia | Anaemia, | | | (normochromic) | | | | | (hyper, hypo or | | | | normochromic) | +-----------------------+-----------------------+-----------------------+ | Renal | Mild polyuria, | Decreased renal blood | | | increased renal blood | flow, | | | | | | | Flow, increased GFR | Decreased GFR, | | | | impaired water | | | | | | | | Excretion | +-----------------------+-----------------------+-----------------------+ | Musculoskeletal | Weakness & muscle | Stiffness, muscle | | | fatigue | fatigue | | | | | | | Increased deep tendon | Decreased deep tendon | | | reflexes | reflexes | | | | | | | Hypercalcemia, | Increased alkaline | | | osteoporosis | phosphatase | +-----------------------+-----------------------+-----------------------+ | CNS | Nervousness, | Lethargy, general | | | hyperkinesia | slowing of mental | | | | | | | Emotional liability | Processes | +-----------------------+-----------------------+-----------------------+ | GIT | Increased appetite, | Decreased appetite, | | | increased freq of | decreased freq of | | | | bowel movement, | | | Bowel movement, | ascities. | | | hypoproteinemia | | +-----------------------+-----------------------+-----------------------+ | Respiratory | Dyspnea, decreased | Pleural effusion, | | | vital capacity | hypoventilation, | | | | | | | | Carbondioxide | | | | retention | +-----------------------+-----------------------+-----------------------+ | CVS | Decreased PVR, | Increased PVR, | | | Increased (HR, SV, | Decreased (HR, SV | | | | | | | CO, pulse pressure), | CO, pulse pressure), | | | CHF, Increased | bradycardia | | | | | | | Inotropic & | Pericardia effusion | | | chronotroipc effects, | | | | angina | | | | | | | | Arrhythmia, | | | | tachycardia | | +-----------------------+-----------------------+-----------------------+ | Eyes | Retraction of upper | Drooping eyelids, | | | lid, wide stare, | perorbital edema, | | | | | | | Periorbital edema, | Large tongue, loss of | | | exophthalmos | temporal ascept | | | | | | | Diplopia face (graves | of eye brow | | | disease) | | +-----------------------+-----------------------+-----------------------+ PVR: peripheral vascular resistance, SV: Stroke volume. HR: Heart rate, CO: Cardiac output, CHF: Congestive heart failure Freq: Frequency, GFR: Glomerular filtration rate. **Hypothyroidism.** Hypothyroidism is a syndrome resulting from lack /deficiency of thyroid hormones and manifested by a slowing down of all body functions though it is reversible. In infants and children, there is growth and developmental retardation which can lead to dwarfism and irreversible mental retardation. In hypothyroidism, there can be enlargement of the thyroid (goiter) or none. Diagnosis is based on laboratory test where low level of free T4 is seen with elevated serum TSH. **Causes Of hypothyroidism** 1\. It can be drug induced e.g drugs that block hormone synthesis leading to mild-moderate hypothyroidism. E.g Lithium, fluoride, thioamide, aminosalicylic acid, phenylbutazone, aminodarone. 2\. Dyshormoogenesis: here there is impaired synthesis of T4 due to enzyme deficiency. There is goiter with mild to severe hypothyroidism. 3\. Radiation, X-ray, thyroidectomy can all lead to destruction or removal of the gland. Here hypothyroidism is severe and no goiter. 4\. It can be congenital, termed CRETINISM, there is iodine deficiency with TSH receptor blocking antibodies, hypothyroidism is severe. 5\. Absence of TSH due to pituitary /hypothalamic disease, Hypothyroidism is mild. 6\. Hashimoto's thyroiditis: an autoimmune disorder that destroys the thyroid. Very common in the western world. Initially there is goiter that resolves, it causes mild to moderate hypothyroidism. **Management of hypothyroidism.** Hypothyroidism caused by drugs can easily be managed by withdrawing the drugs with a short term replacement therapy using levothyroxine given orally once daily. Levothyroxine of all the thyroid preparations are most commonly used. Infants require more thyroid hormones than adults and are given levothyroxine 10-15 µg/kg/day while for adults 1.7 µg/kg/day. Free T4 and TSH levels should be monitored routinely and must be within the normal level and this usually takes 6-8 weeks following initiation of therapy to attain a steady state level in the blood. **Thyroid preparations** These preparations are used in the treatment of hypothyroidism or complete absence of the thyroid gland. These preparations are available either in the synthetic form or they are of animal origin. The synthetic form includes levothyroxine, liothyronine, liotrix. These synthetic forms have a shelf life of about 2 years especially if stored in dark coloured bottles to minimize spontaneous deiodination. Levothyroxine is the most prescribed for thyroid replacement and suppression therapy. It is stable, low cost, lacks allergenic foreign protein and has a long half-life of about 7 days. It is administered once daily orally. It is converted intracelluarly to T3 thus producing both hormones. Liothyronine has a shorter half-life compared to levothyroxine, about 24 hours and hence not recommended for routine replacement therapy. Its short half-life may necessitate multiple daily dosing a higher concentration and greater difficulty in monitoring the thyroid level via laboratory test. Its use is contraindicated in patients with cardiac disease because of the greater risk of cardio toxicity since it has a higher hormone activity. Liothyronine is best for short term suppression of TSH. Animal origin: Dessicated thyroid is marred with several disadvantages such as protein antigenicity, product instability, variable hormone concentration, difficulty in monitoring in the laboratory and an unknown shelf life. Its only advantage appears to be its low cost. Toxicity seen with levothyroxine is directly related to the hormone level. These includes: Restlessness, insomnia, accelerated bone maturation and growth seen especially in children, heat intolerance, tachycardia, unexplained weight loss, atrial fibrillation and accelerated osteoporosis especially in the elderly Levothyroxine is contraindicated in adults with arrhythmias or angina. Either stoppage or reduction of dosage **Hyperthyroidism (thyrotoxicosis)** Hyperthyrodism is exposure to abnormally high level of the thyroid hormone. Causes are; 1\. Graves disease: Most common form of hyperthyroidism, it is an autoimmune disorder in which there is a genetic defect in the suppressor T lymphocyte helper T lipocytes. It triggers antibodies production to thyroidal antigens which stimulates the thyroid. T3 and T4 are elevated while TSH is suppressed. Treatment involves the use of anti-thyroid drugs already discussed. Surgical removal of the gland (Thyroidectomy) is also recommended. Thirdly destruction of the thyroid gland with radioactive iodine. Thyroidectomy is total or near total. Beta blockers are also given propranolol 20-40 mg 6 hourly as the need arises. This helps in controlling tachycardia, hypertension, atrial fibrillation. 2\. Toxic uninodular/multinodular goiter: Also a form of hyperthyroidism. For multinodular goiter, initiate treatment first with anti-thyroid drugs followed by subtotal thyroidectomy. Management is via surgical excision of the gland with radiotherapy. 3\. Subacute thyroiditis: A viral infection of the thyroid gland that leads to the release of stored hormones. It is a transient form of hyperthyroidism that resolves on its own. Supportive therapy is all that is needed. Drugs like propranolol, aspirin, NSAIDs for pain and inflammation. 4\. Thyrotoxicosis facititis: Excessive ingestion of thyroid hormone either accidentally or intentionally. Treatment is supportive therapy. **Anti-thyroid agents** Hyperactivity of the thyroid gland (hyperthyroidism/thyrotoxicosis) and its effects can be antagonizes in several ways. 1\. Interference with the synthesis of the hormone. 2\. Modification of the tissue response to thyroid hormone. 3\. Destruction/removal of all or part of the thyroid gland either by radiation or surgery (thyroidectomy). Agents to be discussed produces their effects either by inhibiting synthesis or via modification of tissue response to the hormone. The agents include Thioamides, anion inhibitors, iodinated contrast media, radioactive iodine, beta blockers. **Thioamides** They include Methimazole, carbamizole and propylthiouracil. Carbamizole (CBZ) is converted invivo to methimazole (MEZ) and is about ten times more effective than propylthiouracil (PTC). **Pharmacokinetics**: MEZ is completely absorbed when given /taken orally and it readily accumulates within the thyroid. Its excretyed via the kidney about 65-70% is seen in the urine within 48 hours. Although its half-life appears short (6 Hours), its dosing frequency remains unchanged because the drug accumulates in the thyroid. The average daily dosing is 30 mg within 24 hours either as a single dose or in three divided doses. This also applies to CBZ, because it is converted invivo to MEZ. Both drugs can cross the placenta and tend to accumulate within the fetal thyroid, hence caution during pregnancy. PTC is also rapidly absorbed orally and peaks within an hour following administration, its bioavailability is about 50-80% possibly due either to first pass effect or incomplete absorption. It has a very short half-life of about 1.5hrs however just like MEZ it accumulates within the thyroid. The drug is excreted via the kidney. The drug is given 100mg adult dose every 6-8 hours. PTC is preferable in pregnancy because is highly protein bound, it crosses the placenta less readily. It is also ideal for breast feeding mothers as secretion in the breast milk is minimal. **Mechanism of action:** Thioamides acts majorly to prevent hormone synthesis by inhibiting the thyroid peroxidase catalyzed reactions hence blocking iodine organification. Secondly the thioamides block the coupling of the iodotyrosines. PTC majorly inhibits peripheral deiodination of T4 to T3, MEZ does this to a lesser extent. These agents block the synthesis and have no effect on the release of the hormones. Hence they have a slow onset of action, often takes about 3 to 4 weeks to see their effects as this is how long it takes for the stores of T4 already synthesized and stored to be depleted. **Adverse effects**: This is seen in about 3 -12% of patients on it. Most common: maculopapular pruritic rash, fever. Rare adverse effects: urticarial rash, vasculitis, arthralgia, lupus-like reaction, cholestatic jaundice, hepatitis, lymphadenopathy, hypoprothrombenemia, poly serositis, and agranulocytosis an idiosyncratic reaction more likely seen in the elderly receiving high dose of MEZ, however this effect is reversible once the drug is withdrawn. Cross sensitivity exist within the thioamides hence switching within may not be beneficial in patients with severe reactions. **Anions Inhibitors** They include perchlorate (CLo4^-^), pertechnetate (Tco4^-^), thiocyanate (SCN^-^). They block the uptake of iodide by the gland competitively inhibiting the iodine transport mechanism. However large doses of iodide can reverse their effects hence effectiveness is uncertain. Potassium perchlorate an anion is useful in patients with iodide-induced hyperthyroidism like amiodarone-induced hyperthyroidism via blockade of the thyroid reuptake of iodide. Adverse effects of potassium perchlorate includes aplastic anaemia hence it is rarely used. I**odides** These were the main stay of therapy prior to the introduction of thioamides. Currently it is rarely used alone but in combination with thioamides. Iodides can inhibit organification and hormone release and decrease the size and vascularity of the hyperplastic thyroid gland. In susceptible individuals, it can induce hyperthyroidism or precipitate hypothyroididsm. It is given at less than 6 mg daily. Inhibition of hormone release is via inhibition of thyroglobulin proteolysis. Its onset of action is within 2-7 days. It is also available as a pre-operative preparation for surgery because of the reduction in size caused by it. They are however not used alone. They should be initiated following onset of thioamides therapy because they can cause an increase in intraglandular stores of iodine and the gland can also escape from the iodide blockade within 2-8 weeks thus there could be severe exacerbation of thyrotoxicosis in the iodine rich gland. **C/I:** Not used alongside radioactive iodine, not used during pregnancy as they cross the placenta and can cause fetal goiter. **Adverse effects**: Though uncommon and reversible on withdrawal of the agent. They include aceneiform rash, swollen salivary glands, mucous membrane ulcerations, conjunctivitis, fever, metallic taste, bleeding disorders and rarely anaphylactoid reactions. **Iodinated contrast media** Ipodate, io-panoic acid (oral) and diatrizoate (i/v) are examples. They act by inhibiting the conversion of T4 to T3 in the liver, kidney, pituitary gland and brain. Hence response seen is profound as in the improvement of the symptoms of thyrotoxicosis, e.g the heart rate returns to normal within 3 days. The dose is 0.5-1 g/day orally. An additional mechanism of action is suppression/inhibition of hormone release due to the release of iodine. They are relatively non-toxic and are useful adjuncts in thyroid storm and good alternatives to iodide or thioamides when these are contra-indicated. Toxicity seen is similar to iodide. **Radioactive iodine** Radioactive iodine is the only isotope ^131^I used in the treatment of thyrotoxicosis. The others are used in diagnosis. When given orally, it is rapidly absorbed, concentrates in the gland and also incorporated within the storage follicles. Its effect is dependent on the emission of beta rays. It has a half-life of about 5 days. Following its use within a few weeks, it begins to destroy the thyroid parenchyma evidenced by epithelial swelling and necrosis, there is also follicular disruption, edema and leukocyte infiltration. It is easy to administer, is effective with a low cost and absence of pain. However radiation induced genetic damage, leukemia and neoplasm can restrict its use in patients with hyperthyroidism that are over 40 years. It is not given in pregnancy or nursing mothers. **Beta blockers** As earlier said, most of the symptoms seen in thyrotoxicosis mimics the sympathetic stimulation hence sympathetic blockers are useful adjuncts such as beta blockers. β blockers without intrinsic sympathetic activity are the agents of choice because they are effective in patients resisitant to guanethidine and reserpine. Propanolol is the drug of choice most widely used. **Some other problems seen with the thyroid gland**. **Thyroid storm:** This is a thyrotoxic crisis with sudden acute exacerbation of all the symptoms of thyrotoxicosis. It is life threatening. Treatment: Propanolol 1-2mg slow iv followed by 40-80mg orally every 6 hours, Diltiazem 90-120 mg orally 3 or 4 times or 5-10 mg/kg i/v, if propanolol is contra indicated. Saturated potassium iodide is also given, this decreases the release of the hormones from the gland, iodinated contrast is a good alternative that blocks the peripheral conversion of T4 to T3. PTC is also added to the regimen as it also blocks hormone synthesis. Corticosteroids like hydrocortisone 50 mg 6 hourly protects against shock and blocks the conversion of T4 to T3. Supportive therapy is also imperative/essential. **Thyrotoxicosis in pregnancy**: Treatment of women of child bearing age with thyrotoxicosis should be surgical removal of part of the gland (subtotal thyroidectomy) alongside Iodine I^131^. During pregnancy, PTC alongside subtotal thyroidectomy during mid-trimester, thyroid supplements will be necessary after the surgery, although the laboratory test will tell. However basically PTC is usually used during pregnancy. Avoid radioiodine because it crosses the placenta. **Neonatal graves disease**: This is graves disease in the new born infant which could be via genetic transmission of the trait to the fetus or via passage of the antibody. It is self-limiting and subsides over 4-12 weeks. Treatment is still necessary prior to the return to normalcy. PTC 5-10 mg/kg/day in 8 hourly divided doses, along with lodine, propranolol in divided doses and supportive therapy. Prednisolone may be added as this will prevent the conversion of T4 to T3. These drugs are gradually withdrawn as the infant improves. **Non-toxic goiter**: Goiter can be non-toxic, absence of excessive hormone and absence of systemic effects. In this syndrome, there is thyroid enlargement without excessive thyroid hormone. Non-toxic form of goiter. The enlargement seen is due to TSH stimulation from inadequate thyroid synthesis most commonly caused by iodine deficiency. Other causes includes dietary goitrogens, neoplasm. Treatment: Best managed by prophylactic administration of iodine, iodized salt is an excellent source of iodine in the diet. Daily intake should be 150-200ug. For that caused by dietary goitrogens, is best to remove or addition of sufficient thyroxine to shut off TSH stimulation. This can help suppress the goiter as well as correct hypothyroidism. **Thyroid neoplasm**: This can be benign or malignant. Appropriate biopsy will tell which category it belongs. Management: Total thyroidectomy plus radioiodine therapy and of cause life time levothyroxine replacement.