Lecture 9.1 - Calcium Metabolism PDF

Summary

This document details the intricacies of calcium metabolism, covering topics such as calcium levels in the body, parathyroid gland anatomy, and the regulation of calcium and phosphate by various hormones, including parathyroid hormone (PTH), calcitriol (Vitamin D), and calcitonin. It also provides an overview of the control of calcium homeostasis.

Full Transcript

Calcium (divalent metal ion): ◦Adult human contains ~1000g of calcium ◦99% is sequestered in bone in the form of hydroxyapatite crystals ◦Skeleton provides: ‣ Structural support ‣ Major reserve of calcium ‣ Helps to buffer serum levels ‣ Relea...

Calcium (divalent metal ion): ◦Adult human contains ~1000g of calcium ◦99% is sequestered in bone in the form of hydroxyapatite crystals ◦Skeleton provides: ‣ Structural support ‣ Major reserve of calcium ‣ Helps to buffer serum levels ‣ Releasing calcium phosphate into interstitium ‣ Uptaking calcium phosphate ◦~300-600mg of calcium is exchanged between bone and ECF each day Plasma calcium levels: ◦Serum total calcium 2.2-2.6 mmol/L (free 1.0-1.3 mmol/L) ◦ECF [Ca2+] a very small fraction of total body calcium (>1 %) ◦Distributed among three interconvertile fractions ◦Biologically active free ionised [Ca2+] closely regulated to 1.0-1.3 mmol/L ◦Most of the calcium in the body is stored in skeleton Anatomy of parathyroid gland: ◦Parathyroid glands are on the posterior surface of the thyroid gland H&E stain - moderate magnification - Parathyroid gland: Regulation of calcium and phosphate ◦Three hormones involved: ‣ Parathyroid hormone (PTH) (main acute regulator of Ca2+) ‣ Calcitriol, also called 1,25-dihydroxycholecalciferol, or 1 alpha, 25-dihydroxyvitamin, D3, 1,25-dihydroxyvitamin D3 and other variants, is the hormonally active metabolite of vitamin D which has three hydroxyl groups. ‣ Calcitonin (thyroid gland) (not very important in humans, except in pregnancy) Produced by C cells in the thyroid Control of calcium homeostasis: PTH synthesis: ◦PTH has no serum binding protein ◦Straight chain polypeptide hormone - Pro-pre-hormone (115AA long), cleaved to 84AA ◦Synthesis is regulated both at transcriptional and post transcriptional levels ‣ Low serum calcium up-regulates gene transcription ‣ High serum calcium down-regulates ‣ Low serum calcium prolongs survival of mRNA (mechanism not known) ◦T1/2 is 4 mins and released PTH cleaved in liver ◦PTH continually synthesised, but little stored ‣ Chief cells degrade hormone as well as synthesis does ‣ Cleavage of PTH in chief cells accelerated by high serum calcium levels Calcium-sensing receptor (CaSR) controls the release of PTH: PTH target organs and physiological effects: ◦Kidney ‣ Decreases loss to urine ◦Gut ‣ Activates vitamin D and hence increases transcellular uptake from GI tract ◦Bone ‣ Increase resorption PTH action in the gut: ◦Dietary intake of calcium is typically 1000 mg/d ‣ Only 30% of which is absorbed by a paracellular uptake effective when [Ca2+] is not limited ‣ Absorption is significantly increased by vitamin D via a transcellular uptake ◦PTH stimulates conversion of vitamin D to its active form (D3) which increases uptake of Ca2+ from gut Calcium balance and bone: ◦Skeleton has two primary functions Structural support and maintaining serum Ca2+ concentration ‣ Maintenance of serum ca2+ concentration is priority Diseases in bone that affect structural integrity have consequences for serum calcium concentration and vice versa ‣ Calcium phosphate crystals found within collagen fibrils Ca2+ + Pi = hydroxyapaptite crystals ◦Bone deposition - osteoblasts produce collagen matrix which is mineralised by hydroxyapatite ◦Bone reabsorption - osteoclasts produce acid micro-environment hydroxyapatite dissolves ◦Bone is dynamic Principles of bone remodelling: ◦Two step process, bone is broken down and reformed ◦Osteoclasts - erode ◦Osteoblasts - form Actions of PTH on bone: ◦1-2 hours PTH stimulates osteolysis ‣ PTH induces osteoblastic cells to synthesise and secrete cytokines on cell surface ‣ Cytokines stimulate differentiation and activity in osteoclasts and protect them from apoptosis ‣ PTH decreases osteoblast activity exposing bony surface to osteoclasts ‣ Reabsorption of mineralised bone and release of Pi and Ca2+ into extracellular fluid Calcitriol - source and activation of vitamin D: Vitamin D - terminology: ◦Calcidiol: ‣ Formed in hepatocytes from: 23-dihydroxyvitamin D Main circulating form of vitamin D ◦Calcitriol: ‣ Formed from calcidiol in kidney 1,25-hydroxyvitamin D Biologically active form of vitamin D ◦Cholecalciferol: ‣ D3 ‣ Form of vitamin D produced by the action of sunlight on skin and in some supplements e.g. from lanolin or lichen ◦Ergocalciferol: ‣ D2 ‣ Form of vitamin D found most commonly in food Vitamin D metabolism - overview: How does Vit D compare to hormones?: ◦Each of the forms of vitamin D is hydrophobic ◦Transported in circulation bound to carrier proteins - acts through a nuclear receptor ◦25-hydroxyvitamin D in the liver T 1/2 life ~ 2 weeks - active form T 1/2 of 5 hours ◦Pre-vitamin bound to carrier small enough to be filtered by the glomerulus and enter PCT where the conversion to active form takes place by enzyme 1a 0 hydroxylase ◦The active form of the hormone is released from the kidney ◦C-1 hydroxylation is under negative feedback to serum calcium levels, elevated calcium prevents C-1 hydroxylation ◦Elevated PTH stimulates C-1 hydroxylation to form ◦Calcitriol (1,25-dihydroxycholecalciferol) Calcitriol (1,23-dihydrocycholecalciferol) on bone, gut and kidney: Too little vitamin D: Calcitonin (3rd hormone) from thyroid: Feedback regulation of serum calcium: Overview - control of calcium homeostasis: Putting this all together - calcium regulation: When calcium balance goes wrong: ◦Hypocalcaemia: ‣ Hyper-excitability of NMJ Pins and needles Tetany (muscle spasms) Paralysis Convulsions ◦Chronic hypercalcaemia: ‣ Renal calculi ‣ Kidney damage ‣ Constipation ‣ Dehydration ‣ Tiredness ‣ Depression Hypercalcaemia: ◦Signs and symptoms - "Bones, stones, groans and psychiatric overtones" ‣ Lethargy ‣ Depression ‣ Constipation ‣ Renal calculi ‣ Frequent urination ‣ Nausea ‣ Cardia arrhythmias Hypercalcaemia and malignancy: ◦Some malignancies can alter Ca2+ homeostasis indirectly via various endocrine factors ◦Most commonly seen in: ‣ Breast cancer ‣ Squamous cell lung cancer ‣ Myeloma ‣ Genito-urinary cancers (renal, cervix, uterus, ovary) ◦BLT-KP - breast, lung, thyroid, kidney, prostate Parathyroid hormone - related peptide (PTHrp): ◦Secreted by some tumour cells e.g. squamous tumours of the lung or head and neck ‣ Binds to parathyroid hormone receptors ‣ Mimics some effects of parathyroid hormone ‣ PTHrp does not increase renal C-1 hydroxylase enzyme, which normally increases concentration of 1,25-dihydroxyvitamin D Measurement of serum Ca2+: ◦Venous blood sample withdrawn into a plain tube (no anticoagulant) ◦Albumin is measured at the same tune ◦Do not use an EDTA or sodium citrate tube - both EDTA and citrate chelates Ca2+

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