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Thyroid FUNCTION
Lesson’s learning outcomes
• evaluate the nature of & function of thyroid
glands; • explain the processes for the synthesis, secretion & transport of T3 & T4; • assess the mechanism of actions & effects of T3 & T4 in the body; • correlate how thyroid hormone secretions are regulated. • discuss effects of hypo- & hyper-secretions of thyroid hormones and the pathological conditions that cause abnormality; & • correlate laboratory assessment and possible treatment. THYROID GLAND ANATOMY
• Positioned in the lower anterior neck • Shaped like a butterfly • Made up of 2 lobes on each side of the trachea, with a band of thyroid tissue –called – isthmus-running anterior to the trachea and bridging the lobes • Fetal thyroid develops • By 11 weeks, thyroid from an outpouching gland begins to of the foregut at the produce measurable base of the tongue and thyroid hormones migrates to its normal location over the thyroid cartilage in the first 4-8 weeks Major sources of iodine
• US intake: 240 - 740 µg/day • If iodine intake drops below 50 µg/day, thyroid gland is unable to manufacture adequate amounts of thyroid hormones Histology of the Thyroid Gland Gland is composed of hollow spheres, called colloid follicles. The thyroid gland contains numerous follicles
Colloid fills the follicle cavities
Follicle cells produce thyroglobulin
Thyroid Hormones • They are derived OH modification of I I
tyrosine. OH I I These are: O
I T 3 I NH2 O tetraiodothyronine T4 NH2 OH I (T4; usually called O
thyroxine) O OH
triiodothyronine (T3) Thyroglobulin is rich in tyrosine Synthesis of thyroid hormones Iodide uptake is under control of TSH via Na/iodide symporter TPO*
TPO: thyroid peroxidase
Forms of iodothyronine 5--deiodinase
• Type 1: most abundant form; mostly in liver
and kidneys; largest contributor to the circulating T3 • Type 2:; found in brain and pituitary; maintains constant level of T3 in CNS • thyroglobulin/tyroxine-binding globulin (TBG)=(70%) o transthyretin- previously called Thyroid binding prealbumin or TBPA (20%) o albumin (10%) and stored in colloid until they are excreted. Protein binding of thyroid hormone
• When released into the circulation,
only 0.04% of T4 and 0.4% of T3 are unbound by proteins and available for hormonal activity •Unbound Thyroid T3 & T4 are called free T3 & freeT4 ( f T3 & fT4) Inhibition of thyroid hormone synthesis • Thiocyanate & perchlorate inhibit Iodine uptake • Iodination of tyrosine residues in thyroglobulin is inhibited by carbimazole & propylthiouracil Peripheral conversion of thyroid hormones • 80% of T3 comes from T4 which is de- iodinated (outer β ring) in the liver, muscles, kidneys • 20% of T3 comes from thyroid glands T4 to T3 conversion is reduced by:
• Systemic illness • Prolonged fasting • β- blockers like propranolol or amiodarone ( 200 mg of this drug contains 75 mg of iodine) T4 to T3 conversion is increased by:
• Drugs that induce hepatic enzyme activity
like phenytoin Control/Regulation of thyroid hormones • Thyroid hormone synthesis and secretion is regulated by two main mechanisms: - an “autoregulation” mechanism, which reflects the available levels of iodine - regulation by the hypothalamus-anterior pituitary-thyroid axis Hypothalamus-hypophyseal regulation • Laboratory assessment of TRH is not clinically useful • Measurement of TSH & fT4 are more useful in assessing hyperthyroid or hypothyroid states Stimuli to release thyroid hormones
T4 is mostly converted to T3 in the liver & kidneys Other Factors Regulating Thyroid Hormone Levels • Diet: a high carbohydrate diet increases T3 levels, resulting in increased metabolic rate (diet-induced thermogenesis).
• Low carbohydrate diets decrease T3 levels,
resulting in decreased metabolic rate. Factors Regulating Thyroid Hormone Levels
• Cold Stress: increases T3 levels in other
animals, but not in humans. • Other stresses: increased or decreased? • Any condition that increases body energy requirements (e.g., pregnancy, prolonged cold) stimulates hypothalamus TRH TSH (Pit) Effects of thyroid hormones
& syndromes of thyroid dysfunction
• Thyroid hormones are essential for normal growth of tissues, including the nervous system. • Lack of thyroid hormone during development results in short stature and mental deficits (cretinism). • Thyroid hormone stimulates basal metabolic rate. WHAT ARE THE SPECIFIC ACTIONS OF THYROID HORMONE ON BODY SYSTEMS? Effects of Thyroid Hormone on Nutrient Sources • Effects on protein synthesis and degradation
• Effects on carbohydrates One Major Target Gene of T3: The Na+/K+ ATPase Pump • Pumps sodium and potassium across cell membranes to maintain resting membrane potential • T3 increases the synthesis of Na+/K+ pumps, markedly increasing ATP consumption. • T3 also acts on mitochondria to increase ATP synthesis • The resulting increased metabolic rate increases thermogenesis (heat production). Thyroid Hormone Actions which Increase Oxygen Consumption
• Increase mitochondrial size, number and
key enzymes • Increase plasma membrane Na-K ATPase activity • Increase futile thermogenic energy cycles • Decrease superoxide dismutase activity Effects of Thyroid Hormones on the Cardiovascular System
• Increase heart rate
• Increase force of cardiac contractions • Increase stroke volume • Increase Cardiac output • Up-regulate catecholamine receptors Effects of Thyroid Hormones on the Respiratory System
• Increase resting respiratory rate
• Increase minute ventilation • Increase ventilatory response to hypercapnia and hypoxia Effects of Thyroid Hormones on the Renal System
• Increase blood flow
• Increase glomerular filtration rate Effects of Thyroid Hormones on Oxygen-Carrying Capacity
• Increase RBC mass
• Increase oxygen dissociation from hemoglobin Effects of Thyroid Hormones on Intermediary Metabolism
• Increase glucose absorption from the GI
tract • Increase carbohydrate, lipid and protein turnover • Down-regulate insulin receptors • Increase substrate availability Effects Thyroid Hormones in Growth and Tissue Development
• Increase growth and maturation of bone
• Increase tooth development and eruption • Increase growth and maturation of epidermis, hair follicles and nails • Increase rate and force of skeletal muscle contraction • Inhibits synthesis and increases degradation of mucopolysaccharides in subcutaneous tissue Effects of Thyroid Hormones on the Nervous System • Critical for normal CNS neuronal development • Enhances wakefulness and alertness • Enhances memory and learning capacity • Required for normal emotional tone • Increase speed and amplitude of peripheral nerve reflexes Effects of Thyroid Hormones on the Reproductive System • Required for normal follicular development and ovulation in the female • Required for the normal maintenance of pregnancy • Required for normal spermatogenesis in the male TESTS FOR THYROID EVALUATION
a. blood tests b. Other tools THYROID STIMULATING HORMONE
• TSH generation assays are capable of diagnosing primary
hypothyroidism with elevated levels of TSH: • 2nd generation TSH immunometric assays- screens hyperthyroidism. • 3rd generation TSH chemiluminometric assay-distinguishes euthyroidism and hyperthyroidism SERUM fT4 & total T4 • measured using RIA, chemiluminometric assay • Euthyroid: 1/3 of binding sites on TBG are occupied by T4 and the remainder are unoccupied • hyperthyroidism, both total and fT4 concentrations are increased; number of unoccupied binding sites on TBG is decreased • In hypothyroidism, opposite An increase in plasma TBG causes increase in bound T4, unoccupied binding sites but no change in fT4; brought by: •High estrogen concentration during pregnancy or in newborn infant •Estrogen therapy •Inherited TBG excess An decrease in plasma TBG causes decrease both in bound T4, unoccupied binding sites but no change in fT4; brought by: •Severe illness •Loss of low-molecular-weight proteins like nephrotic syndrome •Androgen treatment •Inherited TBG deficiency Plasma total or fT3
• Not routinely • In hyperthyroidism, Plasma total or fT 3 is high • preferable to measure fT3 than total T3 THYROGLOBULIN
• A prohormone protein synthesized and
secreted exclusively by thyroid follicular cells. • An ideal tumor marker • Measured by double antibody RIA, ELISA, immunoradiometric assay, immunochemilumiscent assay methods • Result is affected by presence of antithyroglobulin autoantibodies THYROID AUTOIMMUNITY
• Tests for TSH receptor antibodies [ Trab,
TSHRab] • Tests for thyroid stimulating antibodies [ Trab, thyroid stimulating immunoglobulin (TSI)] Prevalence of thyroid autoantibodies antibody Gen Graves’ Autoimmune pop dse hypothyroidism Antithyro 3% 12-30% 35-60% globulin Thyroid 10- 45-80% 80-99% peroxidase 15% Anti-TSH 1-2% 70-100% 6-60% receptor Thyrotropin releasing hormone test • Used to confirm diagnosis of 2º hypothyroidism or rarely used to detect early primary hypothyroidism • May cause allergic reactions Other evaluative thyroid tools Nuclear medicine evaluation
• Radio active iodine is useful in assessing
the metabolic function of the thyroid and for evaluation and treatment of thyroid cancer. Interpretation of RAIU
• High uptake; high TSH = metabolically
active thyroid gland. This also means active hypothalamus-pituitary stimulation • High uptake; undetectable TSH= primary hyperfunction • Low uptake; Low TSH= metabolically inactive thyroid. Other uses of RAIU
• “hot nodules” are NOT thyroid cancer and
take up much radioactive iodine • “cold nodules” or intermediate nodules maybe cancerous or benign. They less likely take up iodine. Thyroid ultrasound
• For characterizatio n of palpable thyroid abnormalities • Can detect less than 1 cm nodules Fine-needle aspiration biopsy
• accurate tool in the
evaluation of thyroid nodules • Allows prompt identification and treatment of thyroid malignancies • Avoids unnecessary surgery in benign cases Manner of reporting FNAB
• Nondiagnostic • Malignant • Suspicious for malignancy • Indeterminate or suspicious for neoplasm • Follicular lesion of undetermined significance • benign Interpretation of thyroid tests Low free T4 Normal free T4 High free T4 Low Secondary Subclinical Hyperthyroidism TSH hypothyroidism hyperthyroidism Secondary severe Nonthyroidal nonthyroidal illness illness Normal Primary Normal Artifact TSH hypothyroidism Severe nonthyroidal Primary hyperthyroidism illness Laboratory draw within 6 h of thyroxine dose High Primary Subclinical Test artifact TSH hypothyroidism hypothyroidism Secondary hyperthyroidism Thyroid hormone resistance DISORDERS OF THE THYROID Hypothyroidism is defined as low free T4 level with a normal or high TSH
HYPOTHYROIDISM Hoarseness, Dyspnea
(Menorrhagia )
Delayed growth (children)
Mental retardation (infants) Due to many metabolic effects of thyroid hormone, hypothyroidism can lead to: • hyponatremia [ due to low ADH secretion] • high CK [due to myopathy] • hyperlipidemia •hyperprolactinemia • macrocytic anemia, with high MCV [ either as a result of a decreased demand for oxygen carrying capacity or autoimmune pernicious anemia] • Reduced sex-hormone-binding globulin (SHBG) • Reduced glomerular filtration rate Types of hypothyroidism
Impairment leads to compensatory ↑ in TSH levels → hypertrophy and hyperplasia of follicular cells → gross enlargement of gland American Thyroid Association Guidelines for hypothyroidism Screening: Measurement of TSH •At age 35 •Every 5 years after age 35 •More frequently with risk factors or symptoms: goiter, family history, lithium or amiodarone use myxedema
• Means “mucous swelling”. • It is a full blown hypothyroid syndrome among adults • if due to iodine deficiency, goiter occurs Thyroid hormone resistance
• An autosomal dominant disorder
characterized by diminished responsiveness of target tissues to thyroid hormone HASHIMOTO THYROIDITIS
• Most common cause
of hypothyroidism • Autoimmune. • Abnormalities with binding of proteins & thyroid hormones • 45-65 years, F:M = 10-20:1 HASHIMOTO THYROIDITIS
• Painless symmetrical enlargement
• Risk of developing B-cell non-Hodgkin’s lymphoma Other concomitant autoimmune diseases • Endocrine and non-endocrine Hashimoto Thyroiditis Pathogenesis
• Immune systems reacts against a variety of
thyroid antigens • Progressive depletion of thyroid epithelial cells which are gradually replaced by mononuclear cells → fibrosis CRETINISM
• it is a severe hypothyroidism in infants.
• it reflects a genetic deficiency of the fetal thyroid gland or maternal factors. CRETINISM
• The child is mentally
retarded, has a short disproportionately sized body and thick tongue and neck cretinism
• Replacement hormone therapy can prevent it to happen. • Developmental abnormalities and mental retardation are not reversible once they appear HYPERTHYROIDISM OR THYROTOXICOSIS Laboratory investigation of suspected hyperthyroidism
• Plasma fT4 and fT3 are elevated & TSH is
low= hyperthyroidism • fT4 normal=T3 thyrotoxicosis • plasma fT4 high, TSH normal = euthyroid hyperthyroxemia Symptoms of thyrotoxicosis increased in metabolic rate evidenced by •heat intolerance • fine tremor •Tachycardia • weight loss • tiredness •Anxiety • sweating • diarrhea Biochemical features of hyperthyroidism • Hypercalcemia • Hypocholesterolemia [ due to LDL clearance] • Hypokalemia • Plasma SHBG is increased • Plasma CK maybe increased with thyrotoxic myopathy Causes of hyperthyroidism
A. Autonomous secretion •Graves’ disease •Toxic multinodular goiter (Plummer’s disease) or a single functioning nodule (occasionally adenoma) •Subacute thyroiditis •Some metastatic thyroid carcinomas Causes of hyperthyroidism
B. Excessive ingestion of thyroid hormones
or iodine •Amiodarone •Thyrotoxicosis factitia ( self-administration of thyroid hormones) •Administration of iodine to a subject with iodine deficiency goiter •Jod-Basedow syndrome Causes of hyperthyroidism
C. Rare causes •Tumor secreting TSH •Struma ovarii ( thyroid tissue in an ovarian teratoma) •Excess hCG (ex. Molar pregnancy or choriocarcinoma) •Pituitary resistance to thyroid hormone rare hyperthyroidism states rare hyperthyroidism states
• Metastatic thyroid carcinoma can produce
thyroid hormones
• Patients with choriocarcinoma or molar
hydatidiform pregnancy have high hCG hormone that can stimulate TSH receptor Graves’ Disease
• Most common cause of thyrotoxicosis.
• Autoimmune disease with genetic susceptibility associated with HLA-B8 and DR3 • Characterized by goiter, ophthalmopathy with exophthalmos and dermopathy Grave’s ophthalmopathy • There is orbital soft tissue swelling, injection of conjunctivae, proptosis , double vision, corneal disease Graves’ Disease
• Female:Male = 7:1 • 3rd to 4th decades • ↑ levels of fT4 &/or T3 • ↓ levels of TSH in blood • ↑ uptake of radioactive iodine • (+) TSIs & TSH receptor Ab Toxic adenoma and multinodular gioter • Caused by autonomously functioning thyroid gland • Treatment includes surgery, radioactive iodine DRUG INDUCED THYROID DYSFUNCTION Amiodarone-induced thyroid disease • Amiodarone is for cardiac arrhythmias • 37% of MW is iodine • Blocks T4 to T3 conversion = hypothyroidism
• Amiodarone can lead to hyperthyroidism in
3% of patients SUBACUTE THYROIDITIS
• A destructive thyroiditis resulting in the
release of preformed thyroid hormones • Subtypes: granulomatous or painful, lymphocytic or silent and painless, and postpartum Euthyroid sick syndrome
• Normal functioning thyroid gland with
abnormal levels of TBG • Low plasma total of fT4 • TSH maybe normal or slightly low or high • TSH response to TRF maybe impaired • There maybe impaired conversion of fT4 to fT3 = difficult interpretation of thyroid function tests Euthyroid hyperthyroxinemia
• Either the plasma total or fT4 concentration
is abnormally raised without clinical evidence of thyroid disease. • Maybe transient or persistent, with high, normal, or low total fT3 concentrations. Nodular disease
• As one ages, chance of developing nodular
disease increases. • Most benign but may develop to toxic multinodular goiter • A toxic multinodular goiter involves an enlargement of the thyroid gland with low TSH and normal thyroxine levels Interpretation of thyroid function tests Total T4 Total T3 fT4 fT3 TBG TSH euthyroid normal normal normal normal normal Normal Hyper normal if 1º thyroid if 2º T3 normal normal normal toxicosis Hypo normal if 1º thyroid if 2º TBG normal normal normal excess TBG normal normal normal T4 normal Normal/ normal normal normal displace ment by drug Thyroid Neoplasms
• Benign, common • Predominant : young to middle women • Presents as solitary thyroid nodule • Painless nodular mass, cold on isotopic scan Papillary Carcinoma
• Commonest thyroid malignancy, 75-85%
• Female:Male = 2.5:1 • Mean age at onset = 20 - 40 yr • May affect children • Prior head & neck radiation exposure • Indolent, slow-growing painless mass cold on isotopic scan • Cervical lymphadenopathy may be presenting feature Papillary Carcinoma Prognosis Excellent but following factors play important role: Age and sex Size Multicentricity Extra-thyroid extension Distant metastasis Total encapsulation, pushing margin of growth & cystic change Anaplastic Carcinoma
producing calcitonin • 5 % of all thyroid malignancies • Sporadic (80%) Medullary Thyroid Carcinoma (MTC)
Sporadic MTC: Middle-aged
adultsFemale:male = 1.3:1 Unilateral involvement of gland +/- cervical lymph node metastases Indolent course with 60-70% 5-yr survival after thyroidectomy Medullary Thyroid Carcinoma (MTC)
Associated with *MEN IIA
Younger patients in twenties Multicentric and bilateral Slow growing Associated with *MEN IIB Even younger patients in teens Aggressive with early metastasis Poor prognosis * Multiple endocrine neoplasia Prognosis of Thyroid Carcinomas Papillary Best prognosis
