NU LIPA Lesson 5 Part 2 - Endocrinology PDF

Lesson 5 – PART 2: ENDOCRINOLOGY PART 2-A : OUTLINE I. Thyroid Gland II. Thyroid Hormone Synthesis III. Hormones Produced by the Thyroid Gland A. Thyroxine B. Triiodothyronine C. Reverse T3 D. Calcitonin IV. Functions of T3 and T4  OUTLINE V. Tests For Thyroid Evaluation A.T...

Lesson 5 – PART 2: ENDOCRINOLOGY PART 2-A : OUTLINE I. Thyroid Gland II. Thyroid Hormone Synthesis III. Hormones Produced by the Thyroid Gland A. Thyroxine B. Triiodothyronine C. Reverse T3 D. Calcitonin IV. Functions of T3 and T4  OUTLINE V. Tests For Thyroid Evaluation A.TSH assay I. TRH Stimulation Test B. Serum T3 and T4 assays J. T3 Uptake test C. Thyroglobulin assay K. Thyroid Hormone D. Reverse T3 assay Binding Ratio (THBR) E. Thyroid Autoimmunity assay L. Free T4 index (FT4I) F. Radioactive Iodine Uptake (RAIU) G. Thyroid Ultrasound H. Fine-Needle Aspiration  OUTLINE VI. Thyroid Gland Disorders A. Hypothyroidism i. Hashimoto’s Thyroiditis B. Hyperthyroidism i. Graves’ Disease ii. T3 Thyrotoxicosis iii. T4 Thyrotoxicosis iv. Toxic Adenoma and Multinodular Goiter v. Reidel’s Thyroiditis OUTLINE C. Drug-Induced Thyroid Dysfunction i. Subclinal Thyroiditis ii. Subacute Thyroiditis D. Nonthyroidal Illness E. Gestational Transient Thyrotoxicosis THYROID GLAND  Thyroid gland ▪ Follicles: functional unit of the thyroid gland ring-shaped structures, in which a single cell band of follicular cells surrounds a closed cavity containing colloid, thyroid hormone, thyroglobulin (Tg), and a variety of other glycoproteins normal thyroid gland weighs about 15 to 25 g  Thyroid gland ▪ consists of two types of cells: a. Follicular cells / thyrocyte single layer of epithelial cells arranged spherically to create a follicle that makes and secretes thyroid hormones, in which these hormones are temporarily stored in the lumen of the follicle b. Parafollicular cells / C cells responsible for the synthesis and secretion of calcitonin, a hormone important in calcium metabolism  Thyroid gland ▪ colloid – viscous homogenous fluid that is rich in nucleoproteins that contains thyroglobulin and enzymes where iodination, exocytosis, and initial phase of hormone secretion occur.  Thyroid gland Underneath: ▪ Parathyroid gland synthesizes hormone, PTH, which regulates serum calcium levels ▪ Recurrent laryngeal nerves stimulates the vocal cords through nerves ▪ By week 11 of gestation, the thyroid gland begins to produce measurable amounts of thyroid hormones, in which these hormones are critical to neurologic development of the fetus.  THYROID HORMONE SYNTHESIS  THYROID HORMONE SYNTHESIS ▪ An intact hypothalamic-pituitary-thyroid (HPT) axis and a ready source of iodide are required for normal thyroid hormone synthesis. ▪ Thyroid hormone synthesis includes the following steps: 1. iodide (i-) trapping by thyroid follicular cells 2. diffusion of iodide to the apex of the cell and transport into the colloid. 3. oxidation of inorganic iodide to iodine and incorporation of iodine into tyrosine residues w/in the thyroglobulin molecules in the colloid THYROID HORMONE SYNTHESIS 4. combination of: two diiodotyrosine (DIT) molecules to form tetraiodothyronine (thyroxine, T4), or monoiodotyrosine (MIT) with DIT to form triiodothyronine (T3) 5. uptake of thyroglobulin from the colloid into the follicular cell by endocytosis, fusion of the thyroglobulin with a lysosome, and proteolysis and release of T4 and T3 6. release of T4 and T3 into the circulation.  THYROID HORMONE SYNTHESIS ▪ TSH modulates the sodium-iodide symporter activity. ▪ An increase in TSH secretion augments the uptake of iodide into the follicular cell. Iodide deficiency increases pump activity Iodide excess inhibits iodide uptake. T3 and T4 are released from thyroglobulin via lysosomal degradation (prootelolysis)  THYROID HORMONE SYNTHESIS ▪ DIT is the preferential iodotyrosine formed; thus, when iodide is abundant, T4 is the predominant form of hormone synthesized and secreted, but when iodide sources are diminished, MIT is produced in greater quantities, leading to increased T3 formation and release. ▪ Thyroid gland has a 5’-deiodinase that converts T4 to T3.  HORMONES PRODUCED BY THE THYROID GLAND ▪ 3,5,3’,5’ tetraiodothyronine (T4) / Thyroxine ▪ 3,5,3’ triiodothyronine (T3) ▪ Reverse T3 ▪ **Calcitonin  Thyroxine ▪ 3,5,3’,5’ tetraiodothyronine (T4) ▪ Formed when coupling two DITs ▪ 100% of circulating T4 is of thyroidal origin ▪ Approximately 110 nmol (85 μg) is produced daily ▪ More predominant thyroid hormone ▪ Precursor for T3 production ▪ 80% of T4 is metabolized into either T3 (35%) or reverse T3 (45%) via monodeiodination  Deiodination ▪ 3,5,3’,5’ tetraiodothyronine (T4) ▪ Formed when coupling two DITs ▪ 100% of circulating T4 is of thyroidal origin ▪ Approximately 110 nmol (85 μg) is produced daily ▪ More predominant thyroid hormone ▪ Precursor for T3 production ▪ 80% of T4 is metabolized into either T3 (35%) or reverse T3 (45%) via monodeiodination Forms oF iodothyronine 5’deiodinase  Triiodothyronine ▪ 3,5,3’ triiodothyronine (T3) ▪ Derived from: o Thyroid gland (20%) - when coupling 1 MIT and 1 DIT o Non-thyroid origin (80%) - from deiodination of T4. ▪ Most active thyroid hormone o 3-8x more metabolically active than thyroxine. ▪ Approximately 10 nmol (8.5 μg) of T3 is produced daily by the thyroid  Triiodothyronine ▪ Has four isoforms of the T3 receptors: o a1, β1 - present in most tissues o a2 - is inhibitory and acts as a negative regulator of thyroid hormone action. o β2 - unique to the pituitary gland and is central in the negative-feedback regulation of TSH by thyroid hormone ▪ Binding of T3 to them promotes thyroid hormone action, presumably by increasing mRNA and protein synthesis  Reverse T3 ▪ 3,3’,5’ triiodothyronine (rT3) ▪ Third major circulating form of thyroid hormone. ▪ A major metabolite of thyroxine which is derived from deiodination of the inner ring of the thyroxine. ▪ An inactive/hibernation hormone, but when in excess, may bind in the thyroid receptor inhibiting the T3 release. ▪ Has a short half-life of 4 hours, and circulates bound to thyroid bonding globulin (TBG) o its formation is considered a disposal pathway in the peripheral metabolism of T4  Reverse T3 ▪ 3,3’,5’ triiodothyronine (rT3) ▪ Third major circulating form of thyroid hormone. ▪ A major metabolite of thyroxine which is derived from deiodination of the inner ring of the thyroxine. ▪ An inactive/hibernation hormone, but when in excess, may bind in the thyroid receptor inhibiting the T3 release. ▪ Has a short half-life of 4 hours, and circulates bound to thyroid bonding globulin (TBG) o its formation is considered a disposal pathway in the peripheral metabolism of T4  Calcitonin ▪ major hypocalcemic hormone ▪ secreted by the parafollicular cells / C cells of the thyroid gland. ▪ regulated by blood calcium levels: ↑↑ o Increased blood calcium promotes calcitonin secretion o Decreased blood calcium suppresses calcitonin secretion  Calcitonin ▪ promotes bone calcium deposition ▪ inhibits PTH and vitamin D3 ▪ elevated in: Medullary thyroid carcinoma (MTC) o MTC originates from the C cells of the thyroid which accounts for: ▪ 1-2% of thyroid cancers, and ▪ 0.57% of thyroid nodules.  FUNCTIONS OF t3 and t4 ▪ Thyroid hormones exerts their metabolic effects via binding to their receptors in the cell’s nucleus. ▪ The target cells of all thyroid hormones are nucleated cells 1. Essential for normal growth & development of the body (i.e., mental dev’t & attainment of sexual maturity) 2. Promote protein synthesis & protein breakdown 3. Maintain normal blood levels of cholesterol & fatty acids Thyroid Hormones  THYROID GLAND DISORDERS Thyroid Gland Disorders  THYROID GLAND DISORDERS Hypothyroidism vs Hyperthyroidism  THYROID GLAND DISORDERS Hypothyroidism vs Hyperthyroidism  THYROID GLAND DISORDERS Hypothyroidism vs Hyperthyroidism THYROID GLAND DISORDERS Thyroid gland disorders & thyroid hormone levels  HYPOTHYROIDISM ▪ defined as a low free T4 level with a normal or high TSH ▪ occurs in 5-15% of women over the age of 65. ▪ the most severe form of hypothyroidism is myxedema, which is a medical emergency  HYPOTHYROIDISM HASHIMOTO’S THYROIDITIS ▪ !most common cause of primary hypothyroidism ▪ an autoimmune disease targeting the thyroid gland,often associated with an enlarged gland, or goiter. ▪ middle-aged women are most commonly affected ▪ !major autoantibody responsible for the destruction of the thyroid gland: o anti-TPO antibody, o anti-thyroglobulin, o anti-microsomal antibody  HYPOTHYROIDISM HASHIMOTO’S THYROIDITIS ▪ According to American Thyroid Association & American Association of Clinical Endocrinologists Guidelines for Hypothyroidism Screening, measurement of TSH: o At age 35 o Every 5 years after the age of 35 o Individuals with risk factors or symptoms: goiter, presence of other autoimmune disease, first-degree relative with autoimmune thyroid dse, lithium use, and amiodarone use  HYPOTHYROIDISM HASHIMOTO’S THYROIDITIS ▪ Hypothyroidism is treated with thyroid hormone replacement therapy. Levothyroxine (T4) is the treatment of choice. ▪ In primary hypothyroidism, the goal of therapy is to achieve a normal TSH level. ▪ If hypothyroidism is of secondary or tertiary origin, TSH levels will not be useful in managing the condition, and a mid normal free T4 level becomes the treatment target.  HYPOTHYROIDISM HASHIMOTO’S THYROIDITIS ▪ Hypothyroidism is treated with thyroid hormone replacement therapy. Levothyroxine (T4) is the treatment of choice. ▪ In primary hypothyroidism, the goal of therapy is to achieve a normal TSH level. ▪ If hypothyroidism is of secondary or tertiary origin, TSH levels will not be useful in managing the condition, and a mid normal free T4 level becomes the treatment target.  HYPOTHYROIDISM Causes of Hypothyroidism  HYPERTHYROIDISM ▪ also known as thyrotoxicosis ▪ results from excess quantities of thyroid hormone ▪ may be caused by: o tumors of the thyroid or rarely of the pituitary or ovaries o inflammation of the thyroid o ingestion of excessive amounts of thyroid hormone or iodine o leakage of stored thyroid hormone from storage in the thyroid follicles  HYPERTHYROIDISM GRAVES’ DISEASE ▪ Also known as Diffuse Toxic Goiter ▪ The most common cause of thyrotoxicosis ▪ Autoimmune condition in which goiter & hyperthyroidism are induced by thyroid- stimulating antibodies that mimic the action of TSH ▪ autoantibody: anti-TSH receptor ▪ !Hallmarks of the condition are bulging eyes (exophthalmos), heat intolerance, increased energy, difficulty sleeping, diarrhea and anxiety.  HYPERTHYROIDISM ▪ Features of Graves’ disease include: o thyrotoxicosis, goiter, o ophthalmopathy (eye changes associated with inflammation and infiltration of periorbital tissue) and o dermopathy (skin changes in the lower extremities that have an orange peel texture). ▪ There is a strong familial disposition to Graves’ disease o 15% of patients will have a close relative with this condition  HYPERTHYROIDISM Findings in Graves’ ophthalmopathy include: o orbital soft tissue swelling, o injection of the conjunctivae, o proptosis (forward protrusion of the eye secondary to infiltration of retro-orbital muscles and fat), o double vision (secondary to orbital muscle involvement and fibrosis), and o corneal disease (often related to trauma because of difficulty closing the eyelids).  HYPERTHYROIDISM Laboratory findings: o high free T4 and/or T3 level o low or undetectable TSH o positive for thyroid-stimulating immunoglobulins and TSH receptor antibodies. o radioactive iodine uptake will be elevated o thyroid scan shows diffuse uptake  HYPERTHYROIDISM Treatment: o Medication: Beta blockers (to control symptoms of adrenergic excess, such as tremor and tachycardia) Propylthiouracil or methimazole (inhibits thyroid hormone synthesis and secretion) The antithyroidal medications, as they are known, carry a risk profile that includes rash and, rarely, hepatotoxicity, agranulocytosis, and aplastic anemia.  HYPERTHYROIDISM Treatment: o Medication: Radioactive iodine and surgery: to destroy or remove enough thyroid tissue so that the patient becomes hypothyroid.  HYPERTHYROIDISM T3 THYROTOXICOSIS ▪ Also known as plummer’s disease ▪ Characterized by a suppressed TSH level associated with a normal to low normal T4 and a high T3 characterizes T3 thyrotoxicosis ▪ More common in a toxic nodule  HYPERTHYROIDISM T4 THYROTOXICOSIS ▪ Characterized by an elevated serum T4 but with serum T3 levels within the reference range or low ▪ Occurs in: o patients with iodine induced thyrotoxicosis o in patients on beta blockers, amiodarone, or large doses of steroids, and o in thyrotoxic patients with NTI HYPERTHYROIDISM  TOXIC ADENOMA AND MULTINODULAR GOITER ▪ caused by autonomously functioning thyroid tissue. ▪ In these instances, neither TSH nor TSI is required to stimulate thyroid hormone production ▪ Thyroid scan: “Hot nodules” that is, they avidly take up radioactive iodine. ▪ Often, the toxic nodules produce so much thyroid hormone that the rest of the thyroid gland is suppressed and metabolically inactive.  reideL’s thyroiditis ▪ Seen in patients with thyroid that becomes “woody” turning it into a stony hard mass. ▪ !Hallmark: presence of fibrosis  DRUG-INDUCED THYROID DYSFUNCTION ▪ Amiodarone-induced Thyroid disease ▪ Amiodarone: a drug used to treat cardiac arrhythmias and may be associated with both hypothyroidism and hyperthyroidism. ▪ Hypothyroidism: o 37% of the molecular weight of amiodarone is iodine o Iodine, when given in large doses, leads to acute inhibition of thyroid hormone prod’n (Wolff-Chaikoff effect) o blocks T4-to-T3 conversion  DRUG-INDUCED THYROID DYSFUNCTION ▪ Hyperthyroidism: o escapes the Wolff-Chaikoff effect and use the excess iodine for thyroid hormone production.  SUBCLINAL THYROIDITIS ▪ there is a mild degree of thyroid dysfunction ▪ TSH is a more sensitive marker than T3/T4 for thyroid disorders!  SUBACUTE THYROIDITIS ▪ Several conditions occur that lead to transient changes in thyroid hormone levels. o inflammation of the thyroid gland, o leakage of stored thyroid hormone, o repair of the gland. ▪ Postpartum thyroiditis o most common form of subacute thyroiditis which occurs in 3% to 16% of women in postpartum period.  SUBACUTE THYROIDITIS o strongly associated with the presence of TPO antibodies and chronic lymphocytic thyroiditis o Thyroid hormone levels usually return to normal after several months ▪ Painless thyroiditis / subacute lymphocytic thyroiditis o shares many characteristics of postpartum thyroiditis, except that there is no associated pregnancy.  SUBACUTE THYROIDITIS ▪ Painful thyroiditis o also called: subacute granulomatous thyroiditis, subacute nonsuppurative thyroiditis, or de Quervain’s thyroiditis o characterized by neck pain, low grade fever, myalgia, a tender diffuse goiter, & swings in thyroid function tests o usually caused by viral infections o TPO antibodies are usually absent o Erythrocyte sedimentation rate and thyroglobulin levels are often elevated  NONTHYROIDAL ILLNESS ▪ Also known as euthyroid sick syndrome ▪ Condition where seriously ill patients can have abnormal thyroid tests even without underlying thyroid pathology. ▪ There is an adaptive response of the thyroid to acute or chronic illness (e.g., sepsis, pneumonia, HIV infection, malignancy, DKA, autoimmune dse, heart failure, etc.)  NONTHYROIDAL ILLNESS ▪ Thyroid hormones are of central importance for thermogenesis, energy homeostasis and metabolism. o Since it is disrupted brought by the condition of the patient, the hypothalamic- pituitary thyroid axis is being dysregulated. ▪ The illness also decreases 5’ monodeiodinase activity, less T4 is converted to active T3. This leads to decreased levels of T3 and higher levels of rT3.  NONTHYROIDAL ILLNESS Laboratory Finding: ▪ In acute illness: low TSH, normal or subnormal T4, very low T3 ▪ In convalescent stage, TSH returns to normal ▪ In severe illness (e.g., myocardial infarction, sepsis), low T4 and T3 (can be called as low T4 and T3 syndrome) There is an adaptive response to reduce metabolic demands and conserve protein stores.  NONTHYROIDAL ILLNESS ▪ As the severity of the illness increases, the serum total T4 falls because of T4-binding protein disruption by inhibitors in the circulation. And this clinical finding means a poor prognosis.  Gestational Transient Thyrotoxicosis ▪ Occurs in 2% of pregnancies ▪ Characterized by more pronounced symptoms and signs of thyrotoxicosis. This condition is frequently associated with first-trimester hyperemesis gravidarum. ▪ Laboratory finding: o prolonged supranormal levels of FT4 levels during pregnancy (due to the influence of hCG)  Gestational Transient Thyrotoxicosis ▪ Serum hCG, which has structural similarity to TSH, has weak thyroid-stimulating activity. o The increase in hCG soon after fertilization results in a small increase in FT4 and T3 concentrations, usually within the normal reference range. o These changes result in a fall in serum TSH during the first trimester; a subnormal serum TSH may be seen in about 20% of mothers who have normal pregnancies. o The peak rise in hCG and the nadir of TSH occur together at about 10 to 12 weeks’ gestation. *nadir - lowest concentration of TSH Characterization of Thyroid Disorders According to Results of Thyroid Function Tests  N, normal; n, negative; V, variable ATG, Antithyroglobulin; aTPO, anti-thyroid peroxidase; FT4, free thyroxine; rT3, reverse triiodothyronine; TBA, TSH receptor–blocking antibody; TBII, TSH-binding inhibiting immunoglobulin; TSI, thyroid-stimulating immunoglobulin. *The spectrum of binding protein abnormalities includes increased or decreased TBG binding, increased or decreased transthyretin binding, and ↑ albumin binding. †Subacute thyroiditis involves a transient period of hyperthyroidism followed by a transient hypothyroid state. MUST TO KNOW! thyroid dyshormonogenesis – genetic condition associated with defect of synthesis of thyroid hormone thyroid hormone resistance – rare condition in which thyroid hormone levels is elevated, but TSH levels are not completely suppressed as expected TSH-dependent hyperthyroidism – 2° hyperthyroidism, in which the serum concentration of TSH is elevated; this is usually due to TSH secreting tumor. PART 2-b : OUTLINE I. Parathyroid Gland II. Calcium Homeostasis III. Vitamin D / Calciferol A. Calcitriol IV. Parathyroid Hormone A. Pth Assay B. Hyperparathyroidism i. Primary Hyperparathyroidism ii. Secondary Hyperparathyroidism  PART 2-b : OUTLINE C. Conditions With Hypercalcemia i. Malignancy-related hypercalcemia ii. Vitamin D intoxication / Hypervitaminosis D iii. Granulomatous disorders D. Hypoparathyroidism V. Metabolic Bone Diseases A. Osteoporosis B. Osteomalacia / Rickets PARATHYROID GLAND  PARATHYROID GLAND ▪ Located at the posterior surface of the thyroid gland ▪ Smallest endocrine gland ▪ Usually 4, two on each lobe of thyroid glands ▪ Small, brownish, ovoid or bean shaped (~3 mm) ▪ Composed of two cells: a. Chief cells: produce, store, and secrete parathyroid hormone (PTH) b. Oxyphil cells: acid-loving cells w/ no known function PARATHYROID GLAND CALCIUM HOMEOSTASIS Principal Organs involved: I. Small intestine o For calcium absorption from the diet since DIET is the only source of calcium in the human body. o Intestinal abnormalities (celiac disease, bowel fistula, short bowel syndromes, bowel resection, etc) may affect calcium absorption. o Adequate dietary calcium intake, the availability of normal amounts of vitamin D, and metabolism are all necessary for optimal calcium absorption. CALCIUM HOMEOSTASIS Principal Organs involved: II. Skeleton (bone) o the chief calcium repository organ, releasing calcium into blood on demand, especially during times of poor intake bones contain 1 kg of calcium and serves as repository for calcium, phosphate, and magnesium contains 99% of body Ca (in hydroxyapatite form) 1% is in the blood which regulates various biochemical events.  CALCIUM HOMEOSTASIS Principal Organs involved: II. Skeleton (bone) In the blood, calcium exists in ionized (50%), proteinbound (40% to plasma proteins), and complexed (10% to citrate and phosphate) forms. The blood pH influences binding with proteins (binding increases with high pH and decreases with low pH). o Bone turn-over or “remodeling” is a regulated and coupled process of simultaneous bone formation and breakdown Too much resorption results in weaker bones (seen in osteoporosis) and too much bone formation can obliterate the marrow space. CALCIUM HOMEOSTASIS Principal Organs involved: III. Kidneys o the principal excretory organ of calcium o where final hydroxylation of calciferol happens o active reabsorption of calcium via PTH Parathyroid gland – secretes PTH Skin – first organ involved in vitamin D synthesis Liver – initial hydroxylation of calciferol CALCIUM HOMEOSTASIS CALCIUM HOMEOSTASIS  VITAMIN D / CALCIFEROL ▪ Both a hormone and vitamin ▪ Steroid hormone ▪ Can be classified as: o Ergocalciferol / Vitamin D2 – found in diet (fishes, dairy products, supplements, and edible mushrooms). o Cholecalciferol / Vitamin D3 - derived from cholesterol that synthesized in the skin following exposure to UVB rays from the sun.  VITAMIN D / CALCIFEROL o Cholecalciferol / Vitamin D3 Tissues for synthesis: skin, liver, kidneys Can also be found in diet; major dietary sources: internal organs (liver) and seafood Breast-fed infants are at risk for vitamin D deficiency, since breast milk is a poor source of vitamin D. hence, the commercially available fortified vit D3 has been introduced ▪ Tissues it affects: gut, bone, kidneys, parathyroids  VITAMIN D / CALCIFEROL ▪ The first organ involved in vit D3 synthesis is skin, specifically the stratum basale, in which cholesterol is converted into 7-dehydrocholesterol by the enzyme DHCR7 (DHC reductase). ▪ With the influence of UV light, 7-DHC is converted into cholecalciferol. ▪ Final hydroxylation of calcidiol in kidney is under PTH regulation.  VITAMIN D / CALCIFEROL Endogenous synthesis of vitamin D is influenced by: a. the amount of sun exposure b. available sunlight (less in northern latitudes) c. skin covering (clothing and sun block) d. age of the individual (older individuals have less effective photobiosynthesis of vitamin D) e. diet  CALCITRIOL ▪ 1,25 dihydroxycholecalciferol; 1,25(OH)2D ▪ the most biologically active metabolite of the Vitamin D sterol family ▪ renal hydroxylation of calcidiol to become calcitriol is the major controlling point in vitamin D metabolism—a step that is regulated by serum phosphate, calcium, and circulating PTH concentrations. o Synthesis is increased when plasma phosphate is low and PTH level is high.  CALCITRIOL ▪ 1,25 dihydroxycholecalciferol; 1,25(OH)2D ▪ the most biologically active metabolite of the Vitamin D sterol family ▪ renal hydroxylation of calcidiol to become calcitriol is the major controlling point in vitamin D metabolism—a step that is regulated by serum phosphate, calcium, and circulating PTH concentrations. o Synthesis is increased when plasma phosphate is low and PTH level is high.  CALCITRIOL ▪ Mechanism of action: o GUT: active absorption of calcium and phosphorus in the small bowel cells Only about 5-10% of calcium is absorbed passively o KIDNEY: reabsorption of calcium and phosphorus o BONE: stimulates differentiation of osteoclast precursors to osteoclasts and stimulates osteoblasts to influence osteoclasts to mobilize bone calcium  CALCITRIOL ▪ 1,25(OH)2D plays an important role in the mineralization of bone, and abnormal bone results when vit D is deficient (e.g., celiac sprue) or its metabolism is defective (e.g., renal failure). ▪ Calcitriol increases blood calcium by augmenting intestinal absorption of calcium. ▪ Of the more than 35 metabolites of vitamin D2 and vitamin D3, only 25(OH)D & 1,25(OH)2D measurements are clinically important. ▪ 25(OH)D is a better marker than vitamin D for evaluation of vitamin D status because of its longer half-life, more limited fluctuation with exposure to sunlight and dietary intake, larger concentration, and ease of measurement.  PARATHYROID HORMONE ▪ the major hypercalcemic hormone produced by the chief cells of the parathyroid gland. ▪ the most important regulator of calcium homeostasis of the blood. ▪ regulates calcium, phosphorus, and magnesium balance within the blood and bone by maintaining a balance between the mineral levels in the blood and the bone.  PARATHYROID HORMONE ▪ helps preserve the normal excitability of muscle and nervous tissue.  PARATHYROID HORMONE ▪ Mechanism of action: o BONE: promotes bone resorption by osteoclasts o KIDNEYS: increases reabsorption of calcium in exchange of phosphorus stimulates renal 1α-hydroxylation of 25-hydroxy vitamin D to produce 1,25(OH)2D o GUT: indirectly stimulates intestinal absorption of calcium via increased synthesis of calcitriol  PARATHYROID HORMONE ▪ The multiple actions of PTH described above are mediated via PTH receptor, located on the cell membrane of target tissues. ▪ PTH secretion is dictated by plasma calcium levels ▪ Parathyroid glands have specialized calcium-sensing receptors (CSRs) that respond to rising or falling calcium levels by increasing or decreasing PTH secretion, respectively.  HYPERPARATHYROIDISM PRIMARY HYPERPARATHYROIDISM ▪ Most common cause of hypercalcemia ▪ Characterized by excessive secretion of PTH in the absence of an appropriate physiologic stimulus and with no response to the physiologic negative- feedback loop of hypercalcemia ▪ Commonly due to parathyroid adenoma ▪ Findings: increased PTH, hypercalcemia, hypercalciuria, phosphaturia, hypophosphatemia, acidosis ▪ Treatment: parathyroidectomy  HYPERPARATHYROIDISM PRIMARY HYPERPARATHYROIDISM ▪ Hypercalcemia is characteristically associated with decreased serum phosphate due to PTH induced phosphate diuretics ▪ This one is frequently accompanied with mild acidosis from decreased renal reabsorption of bicarbonate ▪ Hypercalcemia is attributed to the direct action of PTH on the bone, causing increased resorption.  HYPERPARATHYROIDISM SECONDARY HYPERPARATHYROIDISM ▪ Due to resistance to metabolic actions of PTH as occurs in patients with: o vitamin D deficiency o chronic renal failure o pseudohypoparathyroidism aka Albright’s hereditary osteodystrophy characterized by ineffective PTH action rather than parathyroid dysfunction this results from uncoupling of PTH receptor from the adenylate cyclase due to the mutant stimulatory gene protein  HYPERPARATHYROIDISM SECONDARY HYPERPARATHYROIDISM ▪ Resistance to PTH leads to: parathyroid gland hyperplasia (due to chronic stimulation), and excessive production of PTH ▪ Findings: ↑PTH, ↓ ionized calcium (due to decreased intestinal absorption and increased phosphorus)  CONDITIONS WITH HYPERCALCEMIA Malignancy-related hypercalcemia ▪ can be divided into cases with or without bony metastases With bone metastases: o hematologic malignancies (multiple myeloma, lymphomas, and leukemias), lung carcinoma, renal cell carcinoma, and thyroid carcinoma. o due to direct tumor lysis, secretion of osteoclast activating factor by tumor cells, and secretion of lymphokines with osteoclast potentiating activity such as interleukin-1 and tumor necrosis factor  CONDITIONS WITH HYPERCALCEMIA Without bone metastasis (humoral hypercalcemia of malignancy [HHM]): o renal carcinoma, hepatocellular carcinoma, carcinomas of the head and neck, lung carcinomas, and islet cell tumors of the pancreas. o due to production of PTH-related peptide (PTHrP) which cross reacts with the normal PTH receptors.  CONDITIONS WITH HYPERCALCEMIA Parathyroid hormone–related protein (PTHrP) o substance secreted by cancers that shares structural similarities to the N-terminal portion of human PTH molecule. o bind to the same receptor in the kidney and bone as well as a variety of other tissues. CONDITIONS WITH HYPERCALCEMIA  Vitamin D intoxication / Hypervitaminosis D ▪ due to excessive intake of vitamin supplements ▪ Excess vitamin D causes increased calcium absorption by the intestines, enhanced bone resorption, and hypercalciuria, resulting to suppression of PTH. ▪ Milk-alkali syndrome - due to widespread use of calcium carbonate as prophylaxis for osteoporosis in hospital setting o Manifestations: hypercalcemia, alkalosis, dehydration and renal impairment with mental status changes  HYPoPARATHYROIDISM ▪ Characterized by diminished or absent PTH production by the parathyroid gland leading to: o hypocalcemia, hyperphosphatemia, and o absent to low levels of calcitriol. ▪ Classified as hereditary or acquired ▪ Hereditary: Mutation to PTH and/or CSR gene, Autoimmune, Idiopathic hypoparathyroidism, and DiGeorge syndrome  HYPoPARATHYROIDISM ▪ Acquired: Accidental injury to the parathyroid glands (neck) secondary to neck surgeries and thyroidectomy ▪ Treatment: high doses of vitamin D and calcium; recombinant human PTH  METABOLIC BONE DISEASES OSTEOPOROSIS ▪ most common metabolic disease of bone ▪ defect in the quantity of the bone ▪ a systemic skeletal disorder characterized by decreased organic bone matrix and microarchitectural deterioration of bone tissue, with a subsequent increase in bone fragility (hallmark) and susceptibility to fracture (hip fracture is the most devastating consequence)  METABOLIC BONE DISEASES OSTEOPOROSIS ▪ Risk factors: decreased bone mass, previous fracture, advanced age, family history, long glucocorticoid therapy, cigarette smoking, excess alcohol intake, etc. ▪ Long glucocorticoid therapy: glucocorticoid limits bone formation by inhibiting the action of osteoblast while also inducing osteoblast apoptosis; bone breakdown also increases by stimulating the formation and action of the osteoclast ▪ “Glucocorticoid-induced osteoporosis” is a major source of morbidity associated w/ pharmacologic doses of glucocorticoids METABOLIC BONE DISEASES  METABOLIC BONE DISEASES OSTEOMALACIA / RICKETS ▪ disorders of calcification in which there is failure to mineralize newly formed organic matrix (osteoid) in the mature skeleton, resulting to softening of the bones. ▪ Major categories of diseases that produces osteomalacia / rickets is the vit D deficiency state, hence these two are associated with secondary hyperparathyroidism ▪ Lab findings of 2° hyperparathyroidism can also be seen in those who have rickets and osteomalacia  METABOLIC BONE DISEASES RICKETS ▪ in children (before the closing of the epiphyseal plate) ▪ due to genetic defects in vitamin D metabolism or vitamin D receptor ▪ associated with bony deformities due to bending of long bones ▪ can, however, develop under conditions of adequate amounts of vitamin D. This unique situation may develop from genetic defects in vitamin D metabolism or in the vitamin D receptor.  METABOLIC BONE DISEASES 10 important clinical features in rickets a. Delayed closure of fontanelles b. Frontal bossing c. Dental hypoplasia d. Pectus carinatum e. Swelling in wrist and ankle joints f. Wide sutures g. Craniotabes h. Rachitic rosary i. Harrison’s sulcus j. Bowing of legs METABOLIC BONE DISEASES  METABOLIC BONE DISEASES OSTEOMALACIA ▪ in adult (after the closing of the epiphyseal plate) ▪ bone deformity is not seen in osteomalacia. ▪ Commonly associated with decreased vitamin D ▪ Those of any age who lived indoors with minimal or no sun exposure or those who lack dietary vitamin D are at risk for developing osteomalacia METABOLIC BONE DISEASES Osteoporotic bone is thin In osteomalacia, the total and brittle because there is mass of bone may be too little of it, although the normal but it is soft and composition of the bone is weak because it is not normal properly mineralized quantity down; quality fine quality down; quantity fine