Disorders of the Thyroid Gland Dr.

JM Co

HYPOTHALAMIC-PITUITARY THYROID AXIS: A CLASSIC ENDOCRINE LOOP

o Increase type I 5-deiodinase Promotes thyroid growth It might be important later on in patients with thyroid nodule. If TSH is high, nodules may enlarge. Acts as a thyrocyte survival factor and protects the cells from apoptosis Plays a crucial role in ontogeny DIFFERENCES BETWEEN T4 AND T3 Both total and free T4 are greater than total and free T3, respectively 100% of T4 comes from the thyroid; 20% of T3 comes from the thyroid, 80% from peripheral conversion of T4 Half-life of T4 is 7 days, T3 is 0.75 days T3 is 3x more potent than T4 Thyroxine (T4) contains four iodine atoms. Deiodination leads to production of the potent hormone triiodothyronine (T3), or the inactive hormone reverse T3. THYROID HORMONES WORK BY ALTERING GENE EXPRESSION

The classic endocrine loop (HPT axis) starts at the hypothalamus. It secretes TRH (Thyrotropin-releasing hormone). The hypothalamus will stimulate the pituitary but not the thyroid directly. If you lose your pituitary, your thyroid will fail. The hypothalamus will not backup your thyroid and you will become hypothyroid (underwent pituitary surgery, mass in the pituitary or any other lesion in the pituitary that will stop producing TSH).
Thyroid hormones T4 and T3 feed back to inhibit hypothalamic production of thyrotropin-releasing hormone (TRH) and pituitary production of thyroidstimulating hormone (TSH). TSH stimulates thyroid gland production of T 4 and T3.

FULL NAMES Natural hormones TRH Thyrotropin-releasing hormone TSH Thyroid stimulating hormone or thyrotropin T4 Tetraiodothyronine or Thyroxine T3 Triiodothyronine Synthetic hormones LT4 Levothyroxine LT3 - Liothyronine
The thyroid gland produces two related hormones, thyroxine (T4) and triiodothyronine (T3) These hormones play a critical role in cell differentiation during development and help maintain thermogenic and metabolic homeostasis in the adult Autoimmune disorders of the thyroid gland can stimulate overproduction of thyroid hormones (thyrotoxicosis) or cause glandular destruction and hormone deficiency (hypothyroidism).

Thyroid hormones work by altering gene expression. By altering gene expression, it can cause changes in the body. Hyperthyroid can cause tachycardia, hyperreflexia, weight loss etc. T4 and T3 enter the cell. In the cell, T4 will become T3. It enters the nucleus and stimulates certain nuclear hormone receptors to make gene expression.
The thyroid hormone receptor (TR) and retinoid X receptor (RXR) form heterodimers that bind specifically to thyroid hormone response elements (TRE) in the promoter regions of target genes. In the absence of hormone, TR binds co-repressor (CoR) proteins that silence gene expression. The numbers refer to a series of ordered reactions that occur in response to thyroid hormone: (1) T4 or T 3 enters the nucleus; (2) T3 binding dissociates CoR from TR; (3) Coactivators (CoA) are recruited to the T3-bound receptor; (4) gene expression is altered.

TSH
Stimulates differentiated thyroid functions o Iodine uptake and organification o Thyroglobulin production o Production and release of iodothyronines from the gland

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EVALUATE THYROID ANATOMY AND FUNCTION SEPARATELY You have to evaluate thyroid anatomy and function separately. Anatomy may be abnormal but the function is normal or the other way around. Anatomy Normal
The normal thyroid is 1220 g in size, highly vascular, and soft in consistency. Four parathyroid glands, which produce parathyroid hormone, are located posterior to each pole of the thyroid.

HYPOTHYROIDISM OR THYROTOXICOSIS?

Nodular o Solitary o Multinodular Diffuse Function Normal (non-toxic) Hypofunctioning (non-toxic) Hyperfunctioning (toxic) By combining these, you will arrive at your diagnosis (ex: diffuse toxic goiter, toxic nodular goiter etc.). Remember to evaluate separately! It doesnt mean that just because you have a thyroid nodule, you have a problem with function. It doesnt mean that if you have a large goiter, you have a problem with function; or it doesnt mean that if youre hyperthyroid, you shou ld have a goiter. Some patients have hyperthyroidism but they have small thyroid.

*green circles indicate whether hypothyroidism (left) or thyrotoxicosis (right) Thyrotoxicosis: too much thyroid hormone from any cause Hyperthyroidism: a hyperfunctioning thyroid gland What can cause thyrotoxicosis but not hyperthyroidism? Too much thyroid hormones but thyroid gland is not hyperfunctioning. You can get it from too much tablet. You call it thyrotoxicosis factitia ingestion of exogenous thyroid hormone. There are some diet pills that contain thyroid hormones. Because of this, patients taking these pills experience palpitations and excessive sweating but we really dont know the exact content of these diet pills. Other cause is thyroiditis there is temporary inflammation of the thyroid gland, which is destroyed. Thyroid hormones are suddenly release into the bloodstream. Its not that the thyroid gland is overfunctioning but in the process of being destroyed, it releases thyroid hormones into the bloodstream. INTERPRETING THYROID TESTS IN PRIMARY THYROID DISEASE Primary: problem in the thyroid gland Secondary: problem in the pituitary gland Tertiary: problem in the hypothalamus NORMAL THYROID FUNCTION

Hypothyroidism: arthritis, cold intolerance, depression, dry skin, fatigue, forgetfulness, heavy menstrual periods, infertility, muscle aches Hyperthyroidism: difficulty sleeping, heat intolerance, infertility, irritability, muscle weakness, nervousness, scant menstrual periods

Left side: TSH comes from the brain Right side: FT4 comes from the thyroid

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Here, sometimes the thyroid starts to overproduce thyroid hormones. The brain reacts by starting to decrease TSH to stop the thyroid from making hormones when it is a little bit too much.

Clinical Manifestations: The onset is usually insidious, and the patient may become aware of symptoms only when euthyroidism is restored. Patients with Hashimoto's thyroiditis may present because of goiter rather than symptoms of hypothyroidism. Patients with atrophic thyroiditis or the late stage of Hashimoto's thyroiditis present with symptoms and signs of hypothyroidism. Increased dermal glycosaminoglycan content traps water, giving rise to skin thickening without pitting (myxedema). Typical features include a puffy face with edematous eyelids and nonpitting pretibial edema

The other way around, wherein the thyroid makes too little hormones, the brain reacts by increasing TSH. SUBCLINICAL HYPOTHYROIDISM
Consider treatment: o (+) Anti-TPO antibodies o TSH >10 o Symptoms of hypothyroidism o Goiter o total or LDL cholesterol o Pregnancy o Ovulatory dysfunction with infertility Because the autoimmune process gradually reduces thyroid function, there is a phase of compensation when normal thyroid hormone levels are maintained by a rise in TSH. Though some patients may have minor symptoms, this state is called subclinical hypothyroidism. Later, unbound T4 levels fall and TSH levels rise further; symptoms become more readily apparent at this stage (usually TSH >10 mIU/L), which is referred to as clinical hypothyroidism or overt hypothyroidism.

What causes hypothyroidism? Worldwide: iodine deficiency In iodine sufficient areas: Hashimotos thyroiditis (autoimmune) Iatrogenic: I-131 treatment, thyroidectomy Others o Congenital o Infiltrative disorders: amyloidosis, Riedels thyroiditis o Transient causes: silent thyroiditis (including postpartum thyroiditis), subacute thyroiditis o Secondary: pituitary disorders Iodine deficiency in the Philippines is almost completely eliminated. This is done by putting iodine in our salt. One teaspoon of iodized salt is more than enough; it is about 5 times the amount you need. The daily requirement of iodine for an adult is 150 micrograms.

o Primary hypothyroidism: thyroid hormone replacement indicated

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Laboratory Evaluation: A normal TSH level excludes primary (but not secondary) hypothyroidism. If the TSH is elevated, an unbound T4 level is needed to confirm the presence of clinical hypothyroidism, but T4 is inferior to TSH when used as a screening test, because it will not detect subclinical hypothyroidism.

Typical course of painless thyroiditis with transient thyrotoxicosis

PRIMARY HYPERTHYROIDISM/THYROTOXICOSIS

APPROACH TO HYPERTHYROIDISM Start antithyroid medications o If with eye signs (Graves disease) o If severe hyperthyroidism Get a thyroid scintigraphy o Nodular goiter o No or small goiter o Abrupt onset o Neck pain / tenderness

and

goiter

Primary hyperthyroidism Graves' disease Toxic multinodular goiter Toxic adenoma Functioning thyroid carcinoma metastases Activating mutation of the TSH receptor Activating mutation of Gs (McCune-Albright syndrome) Struma ovarii Drugs: iodine excess (Jod-Basedow phenomenon) Thyrotoxicosis without hyperthyroidism Subacute thyroiditis Silent thyroiditis Other causes of thyroid destruction: amiodarone, radiation, infarction of adenoma Ingestion of excess thyroid hormone (thyrotoxicosis factitia) or thyroid tissue

Thyroid scintigraphy and uptake Technetium-99m o Scintigraphy only (no uptake test) o 20 minute test o Clearer image Iodine 131 o Both scintigraphy and uptake o Image less clear o Patient has to come back the next day for scintigraphy and 24-hour uptake Iodine 125 o Not available locally

Signs and symptoms include features that are common to any cause of thyrotoxicosis as well as those specific for Graves' disease: Symptoms Hyperactivity, irritability, dysphoria Heat intolerance and sweating Palpitations Fatigue and weakness Weight loss with increased appetite Diarrhea Polyuria Oligomenorrhea, loss of libido Signs Tachycardia; atrial fibrillation in the elderly Tremor Goiter Warm, moist skin Muscle weakness, proximal myopathy Lid retraction or lag Gynecomastia *ophthalmopathy and dermopathy specific for Graves' disease

Uptake can help differentiate the cause of hyperthyroidism High uptake o Graves' disease o Choriocarcinoma Low uptake o Subacute thyroiditis o "Silent" thyroiditis o Iodine-loaded patient o LT4 treatment o Uptake values can be used later on for computation of radioactive iodine dose

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NORMAL THYROID

MULTINODULAR GOITER

This is what a normal scan look like. You can see the butterfly-like shape thyroid gland.

In patients with multinodular goiter, there is normal function but has weird shape.

DIFFUSE TOXIC GOITER

AUTONOMOUSLY FUNCTIONING THYROID ADENOMA

In patients with hyperthyroidism, it is darker. Thyroid uptake is higher. Normal for 2 hours is about 5-15%; normal for 24 hours is up to 50%.

In patient with toxic adenoma, there is a nodule which is hypersecreting thyroid hormones.

THYROIDITIS

COLD NODULE

In patients with thyroiditis , the thyroid is destroyed so there wont be anything. The radioactive iodine will not go to the thyroid gland because of the thyroiditis.

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INTERPRETING THYROID TESTS IN SECONDARY THYROID DISEASE SECONDARY HYPOTHYROIDISM The problem is in the pituitary gland.
Secondary hyperthyroidism TSH-secreting pituitary adenoma Thyroid hormone resistance syndrome: occasional patients may have features of thyrotoxicosis Chorionic gonadotropin-secreting tumors Gestational thyrotoxicosisa
a

T4 is low but TSH is normal. If T4 is low, TSH must be elevated. But in here, TSH is still in normal level so there is a problem in the pituitary. There is inappropriately normal TSH. Secondary hyperthyroidism or resistance to thyroid hormone: very rare!

Circulating TSH levels are low in these forms of secondary hyperthyroidism.

This is very rare, around 1 in a million. Treatment is by surgical resection of TSH secreting pituitary adenoma. Take out the adenoma that makes too much hormones.

Secondary hyperthyroidism with inappropriately normal tsh

TSH is low and T4 is low.

Secondary hypothyroidism is usually diagnosed in the context of other anterior pituitary hormone deficiencies; isolated TSH deficiency is very rare. TSH levels may be low, normal, or even slightly increased in secondary hypothyroidism; the latter is due to secretion of immunoactive but bioinactive forms of TSH. The diagnosis is confirmed by detecting a low unbound T4 level. The goal of treatment is to maintain T4 levels in the upper half of the reference range, because TSH levels cannot be used to monitor therapy.

Secondary hypothyroidism: inappropriately normal tsh

TSH is normal but T4 is elevated. The problem is in the pituitary because the pituitary is supposed to react to the high T4 by decreasing TSH.

Hypothyroidism: treatment
Levothyroxine o Most patients will need ~1.6-1.8 mcg/kg/day (IBW) o For elderly patients or patients with CV disorders, start at 12.5-25mcg/day and increase every 4 weeks by 12.5-25mcg until the desired dose is reached (maintenance is ~20% lower for elderly patients) o It is taken daily before breakfast, on an empty stomach. It should not be taken with calcium supplement or iron supplement because it might not be absorbed.

Hyperthyroidism: treatment 1. Medical therapy 2. Radioactive iodine (RAI) therapy 3. Surgery

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ANTITHYROID DRUG THERAPY Thionamides o INHIBIT THYROID HORMONE SYNTHESIS by interfering with thyroid peroxidasemediated iodination of tyrosine residues in thyroglobulin o IMMUNOSUPPRESSIVE EFFECTS: concentrations of antithyrotropin-receptor antibodies decrease with time and may induce apoptosis of intrathyroidal lymphocytes, as well as decrease HLA class II expression Methimazole / Thiamazole (half-life 6h) o More rapid improvement in serum concentrations of T4 and T3 o This is now the first line (before: Propylthiouracil but it is associated with high risk for hepatitis) Propylthiouracil (half-life 1.5h) o Blocks conversion of T4 to T3 within the thyroid and in peripheral tissues (not clinically significant) o Patients who took PTU had higher failure rates for RAI o Recently associated with risk for fatal hepatitis Warn patients regarding adverse reactions o Mild side effects: skin reactions, arthralgias, gastrointestinal symptoms, an abnormal sense of taste, and occasional sialadenitis o Agranulocytosis (0.1-0.4%) o Polyarthritis (1-2%) o Hepatitis (PTU) o Cholestasis (Methimazole) Ask patients to follow-up after 2 weeks o Improvement includes decreased nervousness and palpitations, increased strength, and weight gain

When following up patients Laboratory tests typically repeated after 4-8 weeks of starting / adjusting therapy For hyperthyroid patients: o Check FT4 o If T3 thyrotoxicosis, check FT3 For hypothyroid patients: o Check TSH o For patients with secondary hypothyroidism check FT4 instead Confounding factors Laboratory errors o Always correlate your results with your patients clinical profile o TSH is the most sensitive among the tests and is used for screening o TSH tests available at pathology laboratories st 1 generation TSH: can detect as low as 1mu/L nd 2 generation TSH: can detect as low as 0.1mu/L rd 3 generation TSH: can detect as low as 0.01mu/L th 4 generation TSH: can detect as low as 0.001mu/L o Radioimmunoassays provide the most accurate results (c/o Nuclear Medicine) TSH-RIA, FT3-RIA, FT4-RIA (~1,288.00 each)

DRUG-INDUCED THYROID DISORDERS

Decrease TSH levels o Dopamine, dopamine agonists o Glucocorticoids Increase TSH levels o DA antagonists (eg metoclopramide) Decrease thyroid hormone secretion o Thionamides o Aminoglutethimide o Sunitinib Decrease or increase thyroid hormone secretion o Iodine, iodine containing compounds o Amiodarone o Interferon alpha, interleukin 2 o Lithium Increase TBG levels o Estrogen, tamoxifen, raloxifene o Clofibrate o Fluorouracil, capecitabine, mitotane o Opioids Decrease TBG levels o Androgens o Glucocorticoids Increase hepatic T4 and T3 metabolism (not clinically relevant in patients with intact thyroid function) o Phenobarbital o Phenytoin o Carabamazepine o Rifampin o Sertraline Interfere with thyroid hormone absorption o Calcium

THYROID STORM Rare, life-threatening exacerbation of hyperthyroidism Fever, delirium, seizures, coma, vomiting, diarrhea, jaundice 30% mortality even with treatment Treatment o PTU 600mg loading dose and 200-300mg every 6h o After PTU, saturated solution of potassium iodide (Wolf-Chaikoff effect) Wolf-Chaikoff effect is that if you give iodine to a patient, it can inhibit its own organification. If you give it before PTU, it can worsen the hyperthyroidism. o Beta-blockers o Glucocorticoids (eg dexamethasone 2mg every 6h)
Thyrotoxic crisis is usually precipitated by acute illness (e.g., stroke, infection, trauma, diabetic ketoacidosis), surgery (especially on the thyroid), or radioiodine treatment of a patient with partially treated or untreated hyperthyroidism.

OPHTHALMOPATHY No treatment for mild to moderate ophthalmopathy

becaause there is usually spontaneous improvement

o Smoking cessation o Artificial tears o Eye ointment Severe ophthalmopathy: high-dose glucocorticoids o Prednisone 40-60mg daily o IV methylprednisolone 500-1000mg daily for 1 week

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o o o o o o

Aluminum hydroxide Sevelamer Ferrous sulfate Sucralfate Proton pump inhibitors Raloxifene (?)

ANATOMICAL DISORDERS OF THE TYROID

DIFFUSE NON-TOXIC (SIMPE) GOITER In iodine-deficiency areas: compensatory effort to trap iodide Substernal goiter may obstruct thoracic inlet o Pembertons sign: symptoms of faintness with evidence of facial congestion and external jugular venous obstruction when the arems are raised above the head Trial of TSH suppression with levothyroxine

NON-THYROIDAL ILLNESS SYNDROME (NTIS)) Sick euthyroid syndrome General term used to describe alterations in thyroid hormone concentrations during a variety of acute and chronic illnesses in patients with no previously diagnosed intrinsic thyroid disease Low T3 syndrome o Earliest and most common presentation o Results from decrease T4-to-T3 conversion o Pathogenesis thought to involve cytokines, such as tumor necrosis factor, secreted by inflammatory cells, which inhibits type 1 5'deiodinase. Low T3-T4 o As the illness progresses, T4 declines as well o TSH is low or normal

Diffuse nontoxic goiter- diffuse enlargement of the thyroid occurs in the absence of nodules and hyperthyroidism If thyroid function is preserved, most goiters are asymptomatic. Sudden onset of localized pain and swelling- spontaneous hemorrhage into a cyst or nodule Examination of a diffuse goiter- symmetrically enlarged, nontender, generally soft gland without palpable nodules

Approach to thyroid nodules Is TSH low? o YES Do Scintigraphy Hot nodule no need to biopsy (treat as toxic adenoma) Is nodule >1cm YES Do biopsy Is biopsy malignant or suspicious for malignancy? o YES Do surgery NON-TOXIC MULTINODULAR GOITER Usually asymptomatic If large enough, may cause compressive symptoms:

Any acute, severe illness can cause abnormalities of circulating TSH or thyroid hormone levels in the absence of underlying thyroid disease, making these measurements potentially misleading. The major cause of these hormonal changes is the release of cytokines such as IL-6. Unless a thyroid disorder is strongly suspected, the routine testing of thyroid function should be avoided in acutely ill patients.

- difficulty swallowing, respiratory distress (tracheal compression), or plethora (venous congestion); but these symptoms are uncommon. Symptomatic MNGs are usually extraordinarily large and/or develop fibrotic areas that cause compression.

Caution with contrast agents and other iodine-containing substances (Jod-Basedow effect) Treatment: o T4 suppression is rarely effective o Radioiodine? o Surgery?

Summary of trials on the effects of treatment of ntis

General ICU patients o No benefit of LT4 on general medical patients, patients with acute renal failure, or those undergoing renal transplantation o No benefit of LT3 on burn patients Patients undergoing cardiac surgical procedures o Small studies suggest improved hemodynamic variables with LT3 o Large studies show no benefit of LT3 in patients undergoing cardiac bypass Congestive heart failure o Small uncontrolled study suggested that short-term LT4 therapy increased cardiac output and functional capacity and decreased systemic vascular resistance o Improved hemodynamic variables and neurohumoral profiles with short-term IV LT3 infusion, possibly necessitating supraphysiologic concentrations. o

Jod-Basedow effect- characterized by enhanced thyroid hormone production by autonomous nodules

Radioiodine is used with increasing frequency because it can decrease goiter size and may selectively ablate regions of autonomy. Surgery remains highly effective but is not without risk, particularly in older patients with underlying cardiopulmonary disease.

TOXIC MULTINODULAR GOITER

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The clinical presentation of toxic MNG includes subclinical hyperthyroidism or mild thyrotoxicosis. The patient is usually elderly and may present with atrial fibrillation or palpitations, tachycardia, nervousness, tremor, or weight loss. The TSH level is low. The T4 level may be normal or minimally increased

DIFFERENTIATED THYROID CA
Thyroid carcinoma is the most common malignancy of the endocrine system.

Antithyroid drugs o May stimulate growth of the goiter o Spontaneous remission does not occur Radioiodine? Radioiodine can be used to treat areas of autonomy as well as to decrease the mass of the goiter. Surgery?
Surgery provides definitive treatment of underlying thyrotoxicosis as well as goiter. Patients should be rendered euthyroid using an antithyroid drug before operation.

Papillary CA o Most common o Psammoma bodies, orphan-annie Follicular CA o Difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures Treatment: surgery, RAI, TSH suppression 131 Follow-up with whole body I scan and thyroglobulin

All well-differentiated thyroid cancers should be surgically excised. An initial whole-body scan should be performed about 6 months after thyroid ablation.

HYPERFUNCTIONING SOLITARY NODULE

UNDIFFERENTIATED THYROID CA Anaplastic o Aggressive o Prognosis is poor, and most patients die within 6 months of diagnosis o Chemotherapy and external beam radiatinon (?)
Chemotherapy has been attempted with multiple agents, including anthracyclines and paclitaxel, but it is usually ineffective. External beam radiation therapy can be attempted and continued if tumors are responsive.

Medullary o 3 familial forms: MEN 2A, MEN 2B, and familial MTC without other features of MEN o calcitonin provides a marker of residual or recurrent disease o Treatment primarily surgical
These tumors do not take up radioiodine

A solitary, autonomously functioning thyroid nodule is referred to as toxic adenoma. Thyrotoxicosis is usually mild. The disorder is suggested by the presence of the thyroid nodule, which is generally large enough to be palpable, and by the absence of clinical features suggestive of Graves' disease or other causes of thyrotoxicosis. A thyroid scan provides a definitive diagnostic test- focal uptake in the hyperfunctioning nodule; diminished uptake in the remainder of the gland

Radioiodine ablation is usually the treatment of choice

THYROID LYMPHOMA Arises in the background of Hashimoto's thyroiditis Diffuse large-cell lymphoma is the most common type in the thyroid Surgical resection should be avoided as initial therapy because it may spread disease that is otherwise localized to the thyroid. Sensitive to radiation

Surgical resection is also effective and is usually limited to enucleation of the adenoma or lobectomy

Reference: Harrisons 18th Ed. Chapter 341 Disorders of the Thyroid Gland

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