Lecture 9.1 - Calcium metabolism.pdf

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+