Thyroid Gland Part 2

Physiologic Changes in Thyroid Function Thyroid Function in the Fetus At birth, there is a sudden marked rise in TSH, in T4 and in T3 These parameters gradually return to normal over the first month of life Thyroid Function in Pregnancy There is an increase in urinary iodide clearance; in areas of low dietary iodine intake, this can cause maternal goiter, or when severe, hypothyroidism During pregnancy, there is a rise in TBG, Consequently, serum total T4, and to a lesser extent, total T3 concentrations rise Rising levels of hCG, which has weak TSH receptor agonist activity, contributes to minimal thyroid enlargement peak at approx. 12 weeks resulting in a transient high-normal or even modestly elevated serum free T4 level and a physiologic suppression of serum TSH hCG: Human chorionic gonadotropin

Physiologic Changes in Thyroid Function Effects of Acute & Chronic illness on Thyroid Function (Euthyroid Sick Syndrome) Acute or chronic illness has several striking effects on thyroid function The most common and earliest effect is inhibition of T4 to T3 conversion low serum T3 levels are typically accompanied by total and free T4 levels that are normal cytokines, such as tumor necrosis factor, secreted by inflammatory cells, which inhibits deiodinase enzyme

Abnormalities in Thyroid Hormone Synthesis and Release 1-Dietary Iodine Deficiency and Inherited Defects A very low iodine diet and inherited defects in genes encoding the proteins required for thyroid hormone biosynthesis (dyshormonogenesis) can both result in insufficient hormone production The major adaptation to low iodide intake is the preferential synthesis of T3 rather than T4 In response, the hypothalamic-pituitary-thyroid axis responds to thyroid hormone deficiency by increasing TSH secretion

Abnormalities in Thyroid Hormone Synthesis and Release 1- Dietary Iodine Deficiency and Inherited Defects Consequently, affected individuals typically present with thyroid gland enlargement (goiter) which may be sufficient to compensate for inefficient thyroid hormone production but if not, they develop hypothyroidism Severely affected neonates and infants can suffer the irreversible effects of thyroid hormone deficiency on development that result in cretinism Goiter Cretinism

Abnormalities in Thyroid Hormone Synthesis and Release 2- Effects of Iodine Excess on Hormone Biosynthesis Excess iodide actually inhibits three steps in thyroid hormone production: iodide trapping thyroglobulin iodination and thyroid hormone release from the gland These inhibitory actions are transient, and the normal thyroid gland “escapes” after 10 to 14 days from these effects of excess iodide These autoregulatory effects of iodide insulate physiologic thyroid function from short term fluctuations in iodine intake This effect of iodide has been exploited clinically to produce short-term suppression of thyroid hormone secretion

Thyroid Autoimmunity Autoimmunity is involved in the pathogenesis of many thyroid diseases including: Graves’ disease (hyperthyroidism) long-acting thyroid stimulator, an antibody to the TSH receptor, was found in the sera of patients Hashimoto’s thyroiditis (hypothyroidism) Postpartum thyroiditis, role for female sex hormones in the pathogenesis and certain forms of neonatal thyroid dysfunction Postpartum thyroiditis some women who have postpartum thyroiditis develop symptoms of only hyperthyroidism or only hypothyroidism, but not both. first cause mild signs and symptoms similar to those of an overactive thyroid (hyperthyroidism), Later, as thyroid cells become impaired, mild signs and symptoms of underactive thyroid (hypothyroidism) might develop

Thyroid Autoimmunity There are three major thyroidal autoantigens: Thyroglobulin, TPO, and the TSH receptor Circulating autoantibodies to these antigens are useful markers for thyroid autoimmunity Thyroid peroxidase ( TPO)

Disorders of The Thyroid Patients with thyroid disease usually complain of one or more of the following: Hypothyroidism, symptoms of thyroid hormone deficiency Hyperthyroidism, symptoms of thyroid hormone excess Thyroid enlargement which may be diffuse or nodular;

Hypothyroidism Hypothyroidism is a clinical syndrome resulting from a deficiency of thyroid hormones, which in turn results in a generalized slowing down of metabolic processes Hypothyroidism in infants and children results in: marked slowing of growth and development, with serious permanent consequences, including mental retardation, when it occurs in infancy Hypothyroidism with onset in adulthood causes: generalized decrease in metabolism, diminished oxygen consumption, and deposition of glycosaminoglycans in intracellular spaces, particularly in skin and muscle, producing in extreme cases the clinical picture of myxedema The symptoms and signs of hypothyroidism in adults are reversible with therapy Glycosaminoglycans: are long unbranched polysaccharides consisting of a repeating disaccharide unit.

Myxedema

Other symptoms of Hypothyroidism Cardiovascular signs Bradycardia Pulmonary function shallow, slow respirations Renal function impaired with decreased glomerular filtration rate Neuromuscular system Muscle weakness Central nervous system fatigue, lethargy and inability to concentrate Lethargy: خمول

Hypothyroidism Etiology of hypothyroidism Hypothyroidism may be classified as Primary thyroid failure (most common) Etiology Hashimoto’s thyroiditis: Radioactive iodine therapy for Graves’ disease Subtotal thyroidectomy for Graves’ disease Excessive iodide intake Iodide deficiency Inborn errors of thyroid hormone synthesis Drugs (Lithium) Removal of majority of both lobes leaving behind 4-5 grams (equivalent to the size of a normal thyroid gland) of thyroid tissue on one or both sides The mechanism by which lithium inhibits thyroid hormone release is not well understood. In vitro, lithium decreases colloid droplet formation within thyroid follicular cells, a reflection of decreased pinocytosis of colloid from the follicular lumen

Peripheral resistance to the action of thyroid hormones Secondary due to pituitary TSH deficiency Tertiary due to hypothalamic deficiency of TRH Peripheral resistance to the action of thyroid hormones

Diagnosis of Hypothyroidism If antithyroid antibodies are absent and the indication for therapy uncertain, the medication could be withdrawn for 6 weeks and determinations made for FT4 and TSH. The 6-week period of withdrawal is necessary because of the long half-life of T4 (7 days) and to allow the pituitary gland to recover after a long period of suppression. The 6-week period of withdrawal is necessary because of the long half-life of T4 (7 days) and to allow the pituitary gland to recover after a long period of suppression.

Treatment Hypothyroidism is treated with Levothyroxine (synthetic T4) which is available in pure form and is stable and inexpensive Because T4 is converted to T3 in peripheral tissues, both hormones become available, even though only one is administered The course of untreated hypothyroidism is one of slow deterioration, potentially leading eventually to myxedema coma and death

Hyperthyroidism & Thyrotoxicosis Hyperthyroidism  is a condition in which the thyroid gland produces and secretes excessive amounts of thyroid hormones Thyrotoxicosis is the clinical syndrome that results when tissues are exposed to high levels of circulating thyroid hormones It results in a generalized acceleration of metabolic processes In most instances, thyrotoxicosis is due to hyperactivity of the thyroid gland, or hyperthyroidism

Symptoms of Hyperthyroidism Cardiovascular signs Tachycardia Neuromuscular system Tremor Neurological Anxiety

Graves’ Disease Graves’ disease is the most common form of thyrotoxicosis Females are involved about five times more commonly than males Autoimmune disease of unknown cause The syndrome consists of one or more of the following features: thyrotoxicosis goiter ophthalmopathy dermopathy inflammation of the eyes and bulging eyes.

Treatment of Graves’ Disease Although autoimmune mechanisms are responsible for the syndrome of Graves’ disease, management has been largely directed toward controlling the hyperthyroidism Three good methods are available: Antithyroid Drug therapy inhibiting TPO-mediated iodination of thyroglobulin Surgery Partial or total thyroidectomy and radioactive iodine therapy (131I) destroys thyroid cells A dangerous and short lived fission product. Iodine 131 is a radioisotope with a very short half-life of 8.02 days, making it highly radioactive

Other Forms of Thyrotoxicosis Toxic Adenoma A functioning adenoma hypersecreting T3 and T4 causes hyperthyroidism These lesions start out as a small autonomously functioning nodule that slowly increases in size to produce excessive quantities of thyroid hormones This gradually suppresses endogenous TSH secretion, which results in reduced function of the contralateral lobe of the gland nodules are solid, raised areas in or under the skin that are larger than 0.5 centimeters.

Scanning of Thyroid Gland Normal Graves’ disease Scan using 123I Scan using  Technetium (Tc) Solitary toxic nodule Toxic multinodular goiter Technetium: radioactive metal. I 123:  The isotope's half-life is 13.22 hours Note suppression of contralateral lobe (left) by toxic nodule (right)

Thyroid Hormone Resistance Syndromes Two forms of resistance to thyroid hormones are recognized: Generalized resistance to thyroid hormones (GRTH)- 75% of reported cases are familial mutations in the thyroid hormone receptor transport across cell membrane, thyroid hormone response elements, co-activators, co-repressors Selective pituitary resistance to thyroid hormones (PRTH)- (resistance in the pituitary gland but not in peripheral tissues) (resistance in the pituitary gland and in most or all of the peripheral tissues)

Nontoxic Goiter Nontoxic goiter is not associated with hyperthyroidism Can be diffuse or nodular May result from TSH stimulation due to inadequate thyroid hormone synthesis Worldwide, iodine deficiency remains the most common cause of nontoxic goiter

Thyroiditis Subacute Thyroiditis Chronic Thyroiditis is an acute inflammatory disorder of the thyroid gland most likely due to viral infection self-limited thyroid condition  associated with a triphasic clinical course of hyperthyroidism, hypothyroidism, and return to normal thyroid function no specific treatment is required Chronic Thyroiditis Hashimoto’s thyroiditis autoimmune disorder in which antibodies directed against the thyroid gland lead to chronic inflammation Over time, however, this results in impaired ability of the thyroid gland to produce thyroid hormones

Thyroid Nodules & Thyroid Cancer Thyroid nodules are common Benign Thyroid Nodules But thyroid cancer is a relatively rare condition Follicular carcinoma Medullary carcinoma disease of the C cells (parafollicular cells)

Laboratory Tests Useful in the Differential Diagnosis of Hyperthyroidism RAIU: Radioactive iodine uptake GRTH: generalized resistance to thyroid hormone PRTH: Pituitary resistance to thyroid hormone