Endocrinology - Week 9 Part 1 PDF

Endocrinology Prepared by: Joanna Via Patrize T. Jalocon, RMT, DTA What is Endocrine System? This is a network of ductless glands that secrete hormones directly into the blood. This is also considered as the regulatory system of the body. This is regulated by means of control of ho...

Endocrinology Prepared by: Joanna Via Patrize T. Jalocon, RMT, DTA What is Endocrine System? This is a network of ductless glands that secrete hormones directly into the blood. This is also considered as the regulatory system of the body. This is regulated by means of control of hormone synthesis rather than by degradation. What are hormones? Hormones are chemical signals produced by specialized cells, secreted into the blood stream and carried to a target tissue. Major functions: 1. Maintain the constancy of chemical composition of extracellular and intracellular fluids. 2. Control metabolism. 3. Control growth. 4. Control fertility 5. Respond to stress Hormones Hormones are regulated by the metabolic activity either positive or negative feedback mechanism. Positive feedback mechanism: there is an increased in the product which results to elevation of the activity of the system and production rate. Negative feedback mechanism: increased in the product results to decreased activity of the system and the production rate. Hypothalamus A portion of the brain located in the walls and floor of the third ventricle. It is situated above the pituitary gland and is connected to the posterior pituitary by the pituitary stalk or the infundibulum. This is the link between the nervous system and the endocrine system. The following release different hormones 1. Pineal Gland 2. Pituitary Gland 3. Thyroid Gland 4. Parathyroid Gland 5. Adrenal Gland 6. Reproductive Hormones 7. Pancreas 8. Miscellaneous Hormones Pineal Gland This is attached to the midbrain. Secretes melatonin that decreases the pigmentation of the skin. Pituitary Gland (Hypophysis) Known as “Master Gland”. Location: small cavity in the sphenoid bone of the skull called sella turcica or Turkish saddle. All pituitary hormones have circadian rhythms. Divided into two: 1. Anterior Pituitary 2. Posterior Pituitary Anterior Pituitary (Adenohypophysis) This is the “true endocrine gland”. Regulates the release and production of hormones such as prolactin, growth hormone (GH), gonadotropins (FSH- follicle stimulating hormone; and LH- luteinizing hormone), thyroid stimulating hormone (TSH) and adrenocorticotropic hormone (ACTH) Hormones released in this area are either peptides or glycoproteins. Five Types of Cells by Immunochemical Test: 1. Somatotrophs: secrete growth hormone (GH) 2. Lactotrophs or mammotrophs: secrete prolactin 3. Thyrotrophs: secrete thyroid stimulating hormone (TSH) 4. Gonadotrophs: secrete luteinizing hormone (LH) and follicle stimulating hormone (FSH) 5. Corticotrophs: secrete proopiomelanocortin (POMC) Hormones Secreted by the Anterior Pituitary Gland Growth Hormone (GH)/ Somatotropin The most abundant of all pituitary hormones. The secretion is erratic and occurs in short burst. Overall metabolic effect is to metabolize fat stores while conserving glucose. Hormones Secreted by the Anterior Pituitary Gland Growth Hormone (GH)/ Somatotropin Major stimulus: deep sleep (markedly increased GH) Major inhibitor: somatostatin Increased level: acromegaly, chronic malnutrition, renal disease, cirrhosis and sepsis Decreased: hyperglycemia, obesity and hypothyroidism Hormones Secreted by the Anterior Pituitary Gland Growth Hormone (GH)/ Somatotropin Method: Chemiluminescent immunoassay Reference value (fasting): 50ng/mL or 2210 pmol/L) Diagnostic Tests: Patient Preparation: complete rest 30 minutes before blood collection. Specimen requirement: preferably fasting serum. Diagnostic Tests: For GH deficiency: Screening test: Physical activity test (exercise test) Result: elevated serum GH. Confirmatory test: Insulin Tolerance Test- gold standard Arginine Stimulation Test- 2nd confirmatory test Procedure: 24-hour or nighttime monitoring of GH Interpretation of result: Failure of GH to rise >5ng/mL (adults) and >10ng/mL (child) in all the tests is confirmed GH deficiency. Diagnostic Tests: For Acromegaly: Screening Test: Somatomedin C or insulin-like growth factor 1 (IGF-1) Confirmatory Test: Glucose Suppression Test (75g OGTT or oral glucose tolerance test) *blood is collected every after 30minutes for 2hours; fasting sample is required. Diagnostic Tests: Interpretation of result of acromegaly: Normal response for this test is a suppression of GH less than 1ng/mL If GH fails to decline less than 1ng/mL, it is acromegaly. Failure of GH to be suppressed below 0.3ug/L, accompanied by an elevated IGF-1, is diagnostic of acromegaly. Suppression of GH below 0.3ug/L with normal IGF-1 excludes acromegaly. Suppression of GH but increased IGF-1, requires follow-up and monitoring. Hormones Secreted by the Anterior Pituitary Gland Gonadotropins- Follicle Stimulating Hormone (FSH) and Luteinizing Hormone (LH) Important markers in diagnosing fertility and menstrual cycle disorders. Present in the blood of both male and female at all ages. Elevation of FSH is a clue in the diagnosis of premature menopause. Increased FSH and LH after menopause is due to lack of estrogen. Hormones Secreted by the Anterior Pituitary Gland Thyroid Stimulating Hormone (TSH) Main stimulus for the uptake of iodide by the thyroid gland. Acts to increase the number and size of follicular cells; stimulates thyroid hormone synthesis. TSH in blood levels may contribute in the evaluation of infertility. Hormones Secreted by the Anterior Pituitary Gland Adrenocorticotrophic Hormone (ACTH) This is produced in response to low serum cortisol thus a regulator of adrenal androgen synthesis. Since ACTH is a regulator of adrenal synthesis, deficiency of this will lead to atrophy of the zona glomerulosa and zona reticularis which are the layers of the adrenal cortex. Hormones Secreted by the Anterior Pituitary Gland Adrenocorticotrophic Hormone (ACTH) Highest level is between 6:00AM to 8:00AM; lowest level is between 6:00pm to 11:00pm. ACTH is increased in: Addison’s disease, ectopic tumors, after protein- rich meals. Hormones Secreted by the Anterior Pituitary Gland Adrenocorticotrophic Hormone (ACTH) Specimen requirement: Blood should be collected into prechilled polysterene (plastic) EDTA tubes to prevent degradation of ACTH. Best time for collecting specimen: 8:00AM to 10:00AM Hormones Secreted by the Anterior Pituitary Gland Prolactin (PRL) A pituitary lactogenic hormone; a stress hormone and a direct effector hormone. Major inhibitor: dopamine (which is secreted by the hypothalamus) Consequence of prolactin excess: hypogonadism Increased in: pituitary adenoma, infertility, amenorrhea, galactorrhea, acromegaly, renal failure, PCOS, cirrhosis and secondary hypothyroidism. Hormones Secreted by the Anterior Pituitary Gland Prolactin (PRL) Prolactin serum level >2000mg/dL: pituitary tumor Specimen requirement: blood should be collected 3 to 4 hours after the individual has awakened; fasting sample Highest serum level (during sleep): 4:00AM and 8:00AM; 8:00PM and 10:00PM Method: immunometric assay Hormones Secreted by the Anterior Pituitary Gland Prolactin (PRL) Reference value: Male: 1-20ng/mL (1-20ug/L) Female: 1-25ng/mL (1-25ug/L) Physiologic stimuli (increased): exercise, sleep, stress, postprandially, pain, coitus, pregnancy, nipple stimulation or nursing. Pharmacologic (increased): intake of verapamil, phenothiazines, olanzapine, Prozac, cimetidine and opiate Hormones Secreted by the Anterior Pituitary Gland Notes to Remember! Essentially, you need to obtain TSH and FT4 (free T4) to eliminate primary hypothyroidism as a cause for the elevated prolactin Thyroid hormone replacement therapy will usually return the prolactin to normal plasma level. Three specimens should be obtained at 20-30 minute intervals because of physiologic stimuli. Elevations in prolactin due to physiologic and pharmacologic stimuli rarely exceed 200ng/mL Posterior Pituitary (Neurohypophysis) Capable of releasing the hormones oxytocin and vasopressin but not capable of producing it. ADH is synthesized in the magnicellular neurons of supraoptic and for oxytocin in paraventricular nuclei. Hormones Released by the Posterior Pituitary Gland Oxytocin Stimulates contraction of the gravid uterus at term- “Fergusson reflex”; stimulates muscle contraction during delivery and lactation. There are synthetic preparations of oxytocin and are used to increase weak uterine contractions during labor and to aid in lactation. Hormones Released by the Posterior Pituitary Gland Anti-Diuretic Hormone (ADH)/ Vasopressin/ Arginine Vasopressin (AVP) This acts on what parts of the kidneys? Major function: to maintain osmotic homeostasis by regulating water balance. ADH is a potent pressor agent and affects blood clotting by promoting factor VII release from hepatocytes and factor VIII (von Willebrands factor) release from endothelium. Hormones Released by the Posterior Pituitary Gland Physiologic stimuli to ADH secretion: nausea, cytokine, hypoglycemia, hypercarbia and nicotine. Physiologic stimuli to ADH release: dehydration, physical and emotional stress due to major surgery. Potent physiologic stimuli to ADH release: emetic stimulus Inhibitors of ADH release: ethanol, cortisol, lithium and demeclocycline Reference value: 0.5-2 pg/uL Disorders Associated with Vasopressin/ADH Diabetes Insipidus: there is a deficiency of ADH; results in severe polyuria. (> 3L of urine/day). Clinical picture includes: 1. Normoglycemia 2. Polyuria with low specific gravity 3. Polydipsia (secondary polydipsia) 4. Polyphagia Major Types of Diabetes Insipidus a. True Diabetes Insipidus (Hypothalamic/Neurogenic/Cranial/Central Diabetes Insipidus) There is a deficiency of ADH with normal ADH receptor. Large volume of urine excreted (3-20 L/day) b. Nephrogenic Diabetes Insipidus Characterized by having normal ADH but abnormal ADH receptor. Nephrogenic DI happens when the kidneys failed to respond to normal or elevated ADH levels. May either be congenital or acquired Diagnostic Test for Diabetes Insipidus Overnight Water Deprivation Test (Concentration Test) Fasting: 10:00PM onwards (usually 8 to 12h hours). After 8 to 12 hours without fluid intake, urine osmolality does not rise above 300 mOsm/kg. In neurogenic DI, ADH levels are low and the kidneys rapidly act to conserve water in response to exogenous ADH administration. In nephrogenic DI, ADH levels are either normal or increased and administration of additional ADH has little or no effect on renal water absorption. Syndrome of Inappropriate Antidiuretic Hormone Secretion (SIADH) This refers to the sustained production of ADH in the absence of a known stimuli. Characteristics of SIADH: 1. Decreased urine volume 2. Low plasma osmolality 3. Normal or elevated urine sodium levels (low serum electrolytes) Thyroid Gland This is a butterfly-shaped gland. With two lobes (one on either side of the trachea) located in the lower part of the neck just below the larynx. Isthmus: this is a narrow band that connects the lobes of thyroid gland. Follicle: fundamental structural unit of the thyroid gland. 2 types of cells: follicular cells (T3 and T4); parafollicular or C cells (calcitonin) Thyroglobulin acts as preformed matrix containing tyrosyl groups. Thyroid Hormones Iodine is the most important element in the biosynthesis of thyroid hormones. Thyroid stimulating hormone, as the name implies, stimulates synthesis of thyroid hormones. Free hormones such as FT3 and FT4 are the physiologically active portions of the thyroid hormones. Hypothalamic-pituitary-thyroid axis (HPTA) is the neuroendocrine system that regulates the production and secretion of thyroid hormones. Thyroid Hormones Iodine intake below 50ug/day is an indication of the deficiency of hormone secretion. Thyroid hormones affect synthesis, degradation and intermediate metabolism of adipose tissue and circulating lipids. Functions of thyroid hormones: Tissue growth Mental development and development of CNS Elevated heat production Control of oxygen consumption and for energy conservation Influence CHO and CHON metabolism. Again, what is CHO and CHON? Major Thyroid Hormones 1. Triiodothyronine (T3)/ 3, 5, 3’ triiodothyronine Most active thyroid hormonal activity Used to diagnose T3 thyrotoxicosis. Better indicator of recovery from hyperthyroidism and for the recurrence of hyperthyroidism An increase in plasma level of T3 is the first abnormality seen in cases of hyperthyroidism. Reference value: Adult: 60-160 ug/dL or 0.9-2.46 nmol/L Children 1-14 years old: 105-245 ng/dL or 1.8-3.8 nmol/L Major Thyroid Hormones 1. Tetraiodothyronine (T4)/ 3, 5, 3’ 5’ tetraiodothyronine Principal secretory product. Prohormone for T3 production. All circulating T4 originates in the thyroid gland- it is secreted 100% in the thyroid gland. The amount of serum T4 is a good indicator of the thyroid secretory rate. Reference Value: Adult: 5.5-12.5 ug/dL or 71-161 nmol/L Neonate: 11.8-22.6 ug/dL or 152-292 nmol/L Clinical Disorders Screening for thyroid disorders is recommended when a person reaches 35 years old and every 5 years thereafter. Thyroid autoantibodies: 1. Thyroperoxidase (TPO): involved in tissue destructive process (Hashimoto’s disease). 2. Thyroglobulin (Tg) 3. TSH receptor (TR): involved in Grave’s disease Disorders Associated with the Thyroid Hormone Hyperthyroidism There is an excess circulating thyroid hormone. Signs and symptoms: tachycardia, tremors, weight loss, heat tolerance, emotional lability and menstrual changes Primary hyperthyroidism: there is an elevated T3 and T4 with decreased TSH. Secondary hyperthyroidism: increased FT4 and TSH Hyperthyroidism Thyrotoxicosis: T3 Thyrotoxicosis or T4 Thyrotoxicosis: Plummer’s disease: Group of syndromes FT3 is increased but FT4 is T3 is normal or low but T4 caused by high levels of normal and with low TSH. is increased with low TSH. free thyroid hormones in the circulation. Hyperthyroidism Grave’s disease (diffused toxic Riedel’s thyroiditis: goiter): Most common cause of The thyroid turns into a woody or stony- thyrotoxicosis. hard mass. This is an autoimmune disease in which antibodies are produced that activate the TSH receptor. Features: exophthalmos (bulging eyes) and pritibial myxedema Diagnostic Test: TSH receptor antibody test Hyperthyroidism. Subclinical hyperthyroidism: Subacute granulomatous/ Subacute nonsuppurative thyroiditis/ De Quervain thyroiditis (painful thyroiditis) Associated with neck pain, low- Shows no clinical symptoms but grade fever and swings in thyroid TSH level is low with FT3 and FT4 function tests. of normal levels. TPO antibodies are absent; ESR and thyroglobulin levels are elevated Hypothyroidism Develops whenever insufficient amounts of thyroid hormone are available to tissues. This is treated with thyroid hormone replacement therapy (levothyroxine) Signs and symptoms: bradycardia, weight gain, coarsened skin, cold intolerance and mental dullness Hypothyroidism Primary hypothyroidism: This is due to deficiency of elemental iodine (low T3, T4, TSH) Also caused by destruction of the thyroid gland Other causes: surgical removal of the gland, used of radioactive iodine for hyperthyroidism treatment, radiation exposure, drugs such as lithium. This can be: Hashimoto’s disease or myxedema Hypothyroidism Hashimoto’s Disease (Chronic Myxedema autoimmune thyroiditis Most common cause of primary Peculiar nonpitting swelling of the skin. hypothyroidism. Skin becomes infiltrated by Associated with enlargement of the mucopolysaccharides. thyroid gland (goiter) Clinical features: “puffy” face, weigh gain, Lab result: high TSH and (+) TPO slow speech, eyebrows thinned, dry and antibody yellow skin, and anemia Myxedema coma is the severe form of primary hypothyroidism. Secondary Tertiary hypothyroidism Congenital Subclinical hypothyroidism hypothyroidism/ cretinism hypothyroidism This is due to the Due to hypothalamic Defect in the development Lab result: T3 and T4 pituitary disease or function of the gland. normal; TSH is slightly destruction or increased. pituitary Screening test: T4 adenoma. (decreased) Lab result: Confirmatory test: TSH Lab result: T3, T4, TSH low or (increased) T3 and T4 as well decreased levels Interpretation: TSH value as the TSH are 20 mIU/L (for endocrinologic evaluation to diagnose hypothyroidism) Thyroid Function Tests Thyrotropin Releasing Hormones (TRH) Stimulation Test This measures relationship between the TRH and TSH secretions and also to differentiate euthyroid and hyperthyroid patients who both had undetectable TSH levels. This test is also helpful in the detection of thyroid hormone resistance syndromes and used to confirm borderline cases and euthyroid Grave’s disease. Dose needed: 500ug TRH by IV Increased: primary hypothyroidism Decreased: hyperthyroidism Thyroid Function Tests Thyroid Stimulating Hormone (TSH) Test Most important thyroid function test and the best method for detecting clinically significant thyroid dysfunction. Most clinically sensitive assay for the detection of primary thyroid disorders and helps in the early detection of hypothyroidism. This is used also to differentiate primary hypothyroidism from secondary hypothyroidism and to monitor and adjust thyroid hormone replacement therapy. Reference values: 0.5-5 uU/mL Thyroid Function Tests Increased TSH Decreased TSH Primary hypothyroidism Primary hyperthyroidism Hashimoto’s thyroiditis Secondary and tertiary hypothyroidism Thyrotoxicosis due to pituitary tumor Treated Grave’s disease TSH antibodies Euthyroid sick disease Thyroid hormone resistance Over replacement of thyroid hormone in hypothyroidism Thyroid Function Tests Radioactive Iodine Uptake (RAIU) Used to measure the ability of the thyroid gland to trap iodine and helpful in establishing the cause of hyperthyroidism. Thyroglobulin (Tg) Assay Normally used as a postoperative marker of thyroid cancer Used in monitoring the course of metastatic or recurrence of thyroid cancer. This differentiates subacute thyroiditis (↑ Tg) from thyrotoxicosis factitia (↓ Tg) Thyroid Function Tests Thyroglobulin (Tg) Assay This can be used as a tumor marker for thyroid cancer but always check a simultaneous sample for thyroglobulin antibodies. Increased: untreated and metastatic differentiated thyroid cancer, nodular goiter and hyperthyroidism Decreased: infants with goitorous hypothyroidism and thyrotoxicosis factitia Reference value: Adult- 3-42 ng/mL or ug/mL Infant- 38-48 ng/mL or ug/mL Methods for testing: double-antibody RIA, ELISA, IRMA, Immunochemiluminescent assay (ICMA) Thyroid Function Tests Reverse T3 (rT3) Formed by the removal of one iodine from the inner ring of T4. Endproduct of T4 metabolism; the 3rd major circulating thyroid hormone. Identifies patients with euthyroid sick syndrome (elevated rT3). Used to assess borderline or conflicting laboratory results. Reference value: 38-44 ng/dL Thyroid Function Tests Free Thyroxine Index (FTI or T7) Indirectly assesses the level of FT4 in blood and based on the equilibrium relationship of bound T4 and FT4. Important in correcting euthyroid individuals. Elevated in hyperthyroidism and decreased in hypothyroidism. Reference value: 5.4-9.7 𝑻𝑻𝟒 𝒙 𝑻𝟑𝑼 (%) 𝑭𝑻𝑰 = or TT4 x THBR 𝟏𝟎𝟎 Thyroid Function Tests Total T3 (TT3), Free T3 (FT3) and Free T4 (FT4): FT4 test is used to differentiate drug induced TSH elevation and hypothyroidism. The value of TT3 or FT3 is in confirming hyperthyroidism. Direct/reference method: Equilibrium dialysis (FT4) Thyroid Function Tests T3 Uptake Measures the number of available binding sites of the thyroxine-binding proteins, most notably TBG; a test for TBG (thyroxine binding globulin). T3 uptake is inversely related to TBG- decreased T3 uptake results to elevated TBG and v.v. Increased: hyperthyroidism, euthyroid patients, chronic liver disease Decreased: hypothyroidism, oral contraceptives, pregnancy, acute hepatitis Ref range: 25-35% Thyroid Function Tests Thyroxine Binding Globulin (TBG) Used to confirm results of FT3 and FT4 or abnormalities in the relationship of the total T4 and THBR test. Useful in distinguishing between hyperthyroidism (↑ T4 + Normal TBG) and euthyroidism (↑ T4 and TBG). Hormonal effect: estrogen increases TBG while androgens depresses TBG Increased: euthyroidism, pregnancy and estrogen surge Decreased: anabolic steroids and nephrosis Reference value: 13-39 ug/dL (150-360 nmol/L) Thyroid Function Tests Fine-needle Recombinant Tanned Erythrocyte Serum Pentagastrin (P Aspiration Human TSH Hemagglutination Calcitonin Stimulation Tes Tumor marker Used for the for detecting diagnosis of MTC residual thyroid Most accurate tool in Used to test patients Measure of metastasis in Procedure: an IV the evaluation of with thyroid cancers antithyroglobulin medullary (0.5 ug/kg body w thyroid nodules for the presence of antibodies thyroid is given w/in 5 residual or recurrent carcinoma seconds; blood disease (MTC) samples are Should be collected at basel measured and 1, 2, 5 and 1 before and 6 mins after the sta mos after of infusion. surgery. Summary of Thyroid Disorders and Lab Tests Disorders T3 T4 TSH FT4 rT3 Tg TBG Grave’s Disease ↓ ↑ ↑ ↑ ↑ ↑ N Primary hypothyroidism N/↓ ↓ ↑ ↓ ↓ N/↓ N Hashimoto thyroiditis N/↓ N/↓ ↑ N/↓ ↓ N/↓ N Nonthyroidal illness ↓ N/↓ V V N/↑ N N Thyroid hormone resistance ↑ ↑ N/↑ ↑ ↑ ↑ N Neonatal hypothyroidism ↓ ↓ ↑ ↓ ↓ N/↓ N Notes to Remember Abnormal values of total T3 or T4 must be evaluated with TBG measurement. FT4 and TSH are the best indicators of thyroid status. FT3 and T4 are more specific indicators of thyroid function than the measurements of total hormone because values are not affected by the TBG amount. Euthryroid sick syndrome is acutely ill but without thyroid disease- low T3 and T4, normal or increased TSH but elevated rT3. Notes to Remember In severe hypothyroidism, total CK and LDH values rise moderately. Calcitonin is measured by two-site immunometric assays using monoclonal antibodies, and elevated in autoimmune thyroid disorder, hypercalcemia and all neuroendocrine tumors. Cutoff value for calcitonin: 10ng/L (adults  Reference book: Clinical Chemistry Review Handbook for Medical Technologists Maria Teresa T. Rodriguez, EdD, MSMT (rev. 2018) Thank you! ☺