Parathyroid Glands and Calcium Regulation PDF

Parathyroid Glands and Calcium Regulation to whether Thyroid gland Parathyroid Glands Viveiros | 2025 Topic Outline (1) Overview of calcium homeostasis (...why is it important?) (2) Production and function of pa...

Parathyroid Glands and Calcium Regulation to whether Thyroid gland Parathyroid Glands Viveiros | 2025 Topic Outline (1) Overview of calcium homeostasis (...why is it important?) (2) Production and function of parathyroid hormone (PTH) and its specific action on bone, GI tract, and the kidneys to regulate calcium levels (3) Activation and function of Vitamin D (4) Role of Calcitonin (5) Disruption of calcium homeostasis Hyper- and Hypoparathyroidism Vitamin D deficiency Calcium homeostasis Calcium levels are tightly controlled and regulate essential physiological functions Formation of bones and teeth Skeletal structural integrity Second messenger system activity (intracellular signalling) Trans-membrane potential (neural action) Muscle contraction (smooth, cardiac and skeletal muscle) Blood coagulation (clotting) Problems with calcium (Ca2+) regulation … [Ca2+] Hypercalcemia: High calcium levels Mineralization of soft tissues Polyuria and Polydipsia -PU/PD Cardiac problems..arrhythmia Hypocalcemia: Low calcium levels Weakness (cows) or tetany (dogs, cats) Disruption of calcium Hypotension signaling impairs the function of many systems… Cardiac Neural Muscle Skeletal Calcium distribution in the body Total body calcium  99% Bones* and Teeth  0.9% Soft Tissue Cells  0.1% Extracellular Fluid (ECF) normal total plasma ranges (8.5-10.3 mg/dL).. narrow range Calcium is distributed in 3 forms (fractions)  45% is free in solution as ionized Ca (Ca2+)  50% bound to plasma protein (albumin) - Protein Bound Ca  5% is Complexed Ca –typically with PO4 and SO3 anions Only free ionized Ca (Ca2+) is bioactive *Comparatively little calcium can be readily released from bone, referred to as rapidly exchangeable pool Regulation of calcium levels (1) Total body Ca2+ is regulated by: GItract absorption of Ca2+ Renal excretion (2) The level of free ionized Calcium (Ca2+) in the ECF is regulated by: Exchange between bone and ECF Renal excretion *ECF: Extracellular Fluid Regulation of calcium levels (..the three “3’s”) 3 Tissues GI Tract (dietary intake and fecal excretion) Bone (storage and release) Kidney (urinary excretion) 3 Processes Calcium absorption (GI tract) Calcium resorption or deposition (bone) Calcium reabsorption (kidney) 3 Principal Hormones Parathyroid hormone (PTH) 1,25-dihydroxy Vitamin D3 (Active Vitamin D3 = Calcitriol) Calcitonin Parathyroid gland regulation of plasma Ca2+ Calcium Parathyroid hormone (PTH) Parathyroid glands 4 small oval bodies ~150mg total weight Thyroid gland Located on the posterior Parathyroid Glands surface (back side) of the thyroid gland Produce Parathyroid Hormone (PTH) Thyroid gland Parathyroid gland Chief cells (parenchymal cells) Produce parathyroid hormone (PTH) (1) Parathyroid Hormone (PTH) PTH structure PTH is a protein hormone (84aa) Target Tissues: (1) Skeletal system (Bone) (2) Kidneys (3) GI tract (indirect..via Vitamin D) Functions to control calcium (Ca2+) & Phosphate (PO4-) homeostasis Increases blood Ca2+ Decreases blood PO4- Vitamin D Opposite function to those Parathyroid Hormone of calcitonin PTH synthesis and secretion PTH is a constantly produced (released or degraded) PTH is stored in secretory vesicles and released by exocytosis in response to low extracellular calcium levels PTH response plasma calcium Calcium sensing receptors (CasR) How are calcium levels monitored physiologically? Specific ‘calcium sensing receptors’ enable key tissues to closely monitor the blood calcium levels CasR Expressing Tissues ~Parathyroid cells that secrete PTH ~Thyroid parafollicular cells (C-cells) that secrete calcitonin ~Intestines (determines how much calcium moves in and out of the body) ~Kidneys ~Bone (determines how much calcium moves between the ECF & bone) CasR’s belongs to the C family of G-protein coupled receptors Ca2+ regulation of PTH secretion High Ca2+ Low Ca2+ Ca2+ CasR Ca2+ CasR PTH PTH High serum [Ca2+] promotes Low serum [Ca2+] promotes CasR activation the release of PTH Activation of Phospholipase C and decrease of cAMP Inhibits the release of PTH PTH Function: increase plasma Ca2+ PTH binds specific PTH Receptors (PTHR) on target cells: (1) PTH1R: *Classical PTH receptor High levels expressed in bone and kidney (2) PTH2R: Expressed in the CNS, pancreas, testis and placenta Target Tissues: (1) Bone (1) Kidneys (3) GI tract (indirect: via Vitamin D) Vitamin D Parathyroid Hormone PTH function in bone Osteotclast cells PTH promotes the release (bone resorption) of calcium from bone (bone resorption –’breakdown’) 1.Release of Ca2+ from the rapidly exchangeable pool of calcium (rapid response) 2. Increases activity & survival of existing osteoclast cells 3. Promotes the differentiation, & proliferation of new osteoclast cells (long term response) Osteoblast cells (bone deposition) PTH function in the kidneys PTH increases renal … (1) Reabsorption of calcium in the distal tubules (2) Excretion of phosphate (reduces the phosphate that can bind calcium & thereby increases the amount of free calcium) (3) Induces activation of Vitamin D, which promotes absorption of Ca2+ in the GI tract (2) Vitamin D Two main sources of Vitamin D (1) Produced in skin from a biologically inactive precursor (7-dehydrocholesterol) by Ultraviolet (UV) from sunlight (2) Contained in some foods (fish oils, whole egg…) Both ‘a vitamin’ & ‘a hormone’ ~Vitamin D is not a classic hormone...not produced & secreted by an endocrine gland ~Vitamin D is not a classic vitamin …can be synthesized de novo Lipid soluble molecule ~binds to a typical nuclear receptor, similar to steroid hormones Activates many target genes Vitamin D requires activation Vitamin D UV Light produced in the skin or obtained from Liver Kidney Skin food is NOT bioactive Intestines Vitamin D must be Target cells Cell activated in the Membrane liver & kidney Nucleus Bioactive Vitamin D binds to nuclear receptors on target Lamprecht & Lipkin cells Nature Reviews Bioactive Vitamin D: 1,25(OH)2 Vitamin D3 (Calcitriol) Activation of Vitamin D Vitamin D is activated by the addition of 2 hydroxyl (OH) groups 1st OH-group is added in Liver → 25-Hydroxylase** 25-OH Vitamin D3 2nd OH is added in the Kidneys → 1-Hydroxylase** 1,25(OH)2 Vitamin D3 (Calcitriol) Regulated step based on need for calcium Hydroxylation of the 1-position Makes 1,25 di-OH vitamin D (Calcitriol: Active form of Vitamin D) Hydroxylation of the 24-position Makes 24,25 di-OH vitamin D (Inactive) Activation of Vitamin D Vitamin D is activated by the addition of 2 hydroxyl (OH) groups 1st OH-group added in Liver → 25-Hydroxylase** 25-OH Vitamin D3 2nd OH added in the Kidneys → 1-Hydroxylase** 1,25(OH)2 Vitamin D3 (Calcitriol) Regulated step based on need for calcium Hydroxylation of the 1-position Makes 1,25 di-OH vitamin D (Calcitriol: Active form of Vitamin D) Hydroxylation of the 24-position Makes 24,25 di-OH vitamin D (Inactive) Regulation 1-hydroxylase in the kidney 1-hydroxylase 25-hydroxy-Vit D 1,25-dihydroxy-Vit D (Calcitriol) Enzyme availability can be rate limiting, especially in kidney disease (a calcitriol-deficient state) & some nutritional imbalances such as a diet with excess phosphate and inadequate Ca2+ 1-hydroxylase enzyme is stimulated by: Parathyroid hormone (PTH) Low plasma ionized calcium (1,25 (OH)2 D3) Low plasma ionized phosphate Prolactin (during lactation) 1-hydroxylase enzyme is inhibited by: When plasma ionized High plasma ionized calcium calcium is high, renal hydroxylation produces an High plasma ionized phosphate inactive form: 24,25(OH)2 Vitamin D3 Function of active Vitamin D: 1,25-(OH)2-D (calcitriol) Acts by binding to a specific Vitamin D Receptor (VDR) (1) Absorption of Ca in GI (2) Resorption of Ca in Bone Promotes gene expression of Increases osteoclastic and Ca transport proteins (TRPV6 & osteocytic activity (osteolysis) calbidin) Allows ingested Ca to be absorbed Promotes release of Ca2+ from against what would otherwise be an bone unfavorable Ca gradient Osteoclast cells (bone resorption) ` Function of activated Vitamin D (1) Increases total body calcium by increasing GI absorption of calcium Dose-dependent response Slow, long-lasting response Adjusts calcium intake from diet to match needs via changes in ratio of active/inactive Vitamin D (2) Increases ECF ionized calcium by enhancing response of bone to PTH (resorption) (3) Calcitonin A peptide hormone (32 aa) Calcitonin functions to LOWER plasma Ca2+ Produced in the parafollicular cells (‘C-cells’) of the thyroid Calcitonin effects on bone remodelling is opposite to PTH (1) Inhibits activity of osteoclasts (decreases bone resorption) (2) Decreases Ca2+ image reabsorption in the kidney (increases Ca2+ excretion) (3) Inhibits Ca2+ absorption in the GI tract Regulation of Calcitonin Secretion Calcitonin secretion is regulated by plasma Ca2+ levels Low Ca2+ High Ca2+ Ca2+ CasR Ca2+ CasR Calcitonin Calcitonin Low serum [Ca2+] inhibits the High serum [Ca2+] promotes release of calcitonin the release of calcitonin LOWER plasma Ca2+ Calcitonin function Calcitonin functions by binding to a specific Calcitonin Receptors G-coupled membrane bound receptors Expressed in bone, kidney & brain Main action: Inhibiting osteoclast activity (…decreases bone resorption) Physiological role of calcitonin seems to be small While it could theoretically act as a physiologic antagonist to PTH, it does not usually do so Evidence suggests it is important in control of bone remodeling Clinical importance: Administration of exogenous calcitonin: Treatment for intractable hypercalcemia Bone diseases characterized by excessive bone resorption Parathyroid gland regulation of plasma Ca 2+ Calcium Parathyroid hormone (PTH) 1 2 3 Disruption of calcium homeostasis Hypoparathyroidism A rare condition usually caused by autoimmune disease Low PTH secretion results in low plasma Ca2+ levels..hypocalcemia Low calcium causes disrupts neuromuscular excitability (Tetany: muscle spasms … very low Ca2+ is lethal) Hyperparathyroidism Primary form usually due to hypersecreting parathyroid tumor High PTH can result in hypercalcemia Chronic renal disease or Vitamin D deficiency causing hypocalcemia, which in turn promotes high PTH production Clinical problems with high PTH levels with elevated Ca2+ 1. Depressed muscle and nerve excitability High ECF [Ca2+] 2. Increased risk of fractures Demineralization of bone 2. Risk of kidney stones High concentration of calcium in renal filtrate High PTH and Vitamin D Deficiency Impairs absorption of calcium in the GI tract The resulting high PTH causes bone demineralization In children, result is rickets In adults result in osteomalacia (softening of bones) Normal Anatomy Rickets  View Image Clinical problem with low Ca2+. Example: Lactating dairy cow) 2-year old Holstein Dairy Cow Complaint: “Downer” Cow (= a mature dairy cow that is still recumbent >3 hours after calving) History: Calved 24 hours ago; never got up Physical exam: Recumbent & will not rise but otherwise normal for 1-day post-partum Clinical pathology: Calcium 6.8 mg/dL (Normal: 8.5-10) ------------------------- Average milk production ~10 gallons per day ….(4-5 gm calcium loss daily) Q: What is the expected response of calcium regulatory hormones to this hypocalcemia? Q: What are possible treatment options? Learning Objectives Know the regulation function of each hormone (1) Parathyroid Hormone (PTH) (2) active Vitamin D (3) Calcitonin How does its action on bone, kidney & GI tract alter plasma calcium? Roles of PTH, Vitamin D, and calcitonin in response to Low calcium levels (Hypocalcemia) High calcium levels (Hypercalcemia)