内分泌生殖系统教学课件：09 血钙调节与代谢.ppt

单击此处编辑母版标题样式,单击此处编辑母版文本样式,第二级,第三级,第四级,第五级,*,*,Hormonal Regulation Of Plasma Calcium And Calcium Metabolism,1,1.The significance of maintaining plasma calcium levels.,I The normal value and source of plasma calcium;,II The structure,functions and endocrinology of bone;,2.The hormonal regulation of plasma calcium,:,I Parathyroid hormone:parathyroid glands;secretion of parathyroid hormone;actions of parathyroid hormone;parathyroid hormone related peptide.,II Calcitriol:source and activation of vitamin D;vitamin D and calcitriol in blood,；,action of calcitriol.,III other hormones.,3.Disorders of calcium metabolism and metabolic bone disease:,I Disorders of hypocalcaemia:vitamin D deficiency;parathyroid hormone deficiency.,II Diseases of bone:osteoporosis;osteomalacia and rickets;Pagets disease.,4.Regulation of serum phosphate.,2,1.The significance of maintaining plasma,calcium levels.,3,CALCIUM,2,%,of body weight,99%in bones,1%in body fluids,Plasma,(Extracellular,fluid,),2.25 2.75 mmol/l,Cell,(Intracellular,fluid,),10,-8,10,-7,mol/l,=,10,-,5,10,-,4,m,mol/l,4,5,PLASMA CALCIUM,diffusible,48%(50%)Ca,2+,ionized,6%(10%)combined with anions(citrate,phosphate)non-dissociated,nondiffusible,4640%)combined with plasma proteins,combination with proteins depends on pH,0.2 mmol/l Ca,2+,on each pH unit,6,Plasma Calcium Regulation,Free calcium is tightly regulated(,5%),Too low=neuronal hyper-excitability,Too high=neuronal depression,Control points for calcium,Absorption Via intestines,Excretion Via urine,Temporary storage Via bones,7,Calcium Balance,Intake=output,Negative,calcium balance:Output intake,Neg Ca,2+,balance leads to,osteoporosis,Positive,calcium balance:Intake output,Occurs during,growth,Calcium is essential,we cant synthesize it,8,Calcium and the Cell,Translocation across the plasma membrane,Translocation across the ER and mitochondrion;Ca,2+,ATPase in ER and plasma membrane,9,ROLE OF CALCIUM,excitability of cell membranes,neuromuscular transmission and muscle contraction,releasing of transmitters from synapses,“second messenger”,stimulates secretory activity of exocrine glands and releasing of hormones,contractility of myocard,blood coagulation,10,Changes in Ca,2+,plasma level,Hypocalcemia,Muscle tetany carpopedal spasm,Na,+,inflow myocardium excitability and conductibility,；,Ca,2+,inflow plateau phase of action potential,Increased cell membrane permeability,Impaired blood clotting,Hypercalcemia,Depression of nervous system,reflex activity,Increased heart contractility,Formation of calcium phosphate crystalls,（,Kidney stones,and ectopic calcification,）,11,Bones reservoir of calcium,99%of skeletal calcium forms stable bone(not exchangeable with the Ca in extracellular fluid),1%is in the form of releasable pool of Ca,Balance of deposition and resorption,Osteoblasts,bone-forming,cells responsible for bone deposition,Secrete type I collagen,Differentiate into osteosytes,Osteoclasts,“bone-eating”cells,that resorb the previously formed bone,12,Osteoblast and Osteoclast Function,Osteoblasts,Bone formation,Synthesis of matrix proteins,Type I collagen,Osteocalcin,Others,Mineralization,Activation of osteoclasts via RANKL production,Osteoclasts,Bone resorption,Degradation of proteins by enzymes,Acidification,RANK is activated by RANKL,and this leads to cells differentiation to osteoclasts,13,Regulation of osteoblasts function,Stimulation,PTH(fast reaction-activation of calcium pump?pumping Ca to ECF),1,25 Dihydrocholecalciferol,IL-1,T3,T4,hGH,IGF-1(insuline-like growth factor),PGE,2,(prostaglandine),TNF(tumor necrosis factor),Estrogens,Inhibition,Corticosteroids,15,Regulation of osteoclasts function,Stimulation,PTH(not directly through stimulation of osteoblasts),1,25 Dihydrocholecalciferol(not directly through stimulation of osteoblasts),IL-6,IL-11,Inhibition,Calcitonin(directly receptors),Estrogens(by inhibiting production of certain cytokines),TGF-,(tranforming growth factor),PGE,2,(prostaglandine),16,2,.The hormonal regulation of,plasma calcium,17,Regulation of,calcium,metabolism,Parathyroid hormone,Calcitonin,Vitamin D,18,Parathormon,19,Parathyroid Hormone Structure,Synthesized in the 4 para-thyroid glands,PreProPTH Regulator of Ca,2+,homeostasis,PTH t,1/2,(half life)is 2-3 min,Liver(2/3,rds,)and kidney(1/3,rd,)are major sites of fragmentation,20,Parathyroid Glands,21,22,28,W.F.Ganong:Review of Medical Physiology 2003 20th Ed.#188 fig.21-10,Mechanism of Action of PTH,PTH binds to a G protein-coupled receptor.,Binding of PTH to its receptor activates 2 signaling pathways:,-increased cyclic AMP,-increased phospholipase C,Activation of PKA appears to be sufficient to decrease,bone mineralization,Both PKA and PKC activity appear to be required for,increased resorption of calcium,by the kidneys,24,Actions of PTH:Bone,PTH acts to,increase degradation of bone,(release of calcium).,-Rapid action,-Delayed action,-causes osteoblasts to release cytokines,which,stimulate osteoclast activity,-stimulates bone stem cells to,develop into osteoclasts,-,net result,:increased release of calcium from bone,-effects on bone are dependent upon presence of vitamin D,25,Actions,of PTH:Kidney,PTH acts on the kidney,the reabsorption,of calcium,(excretion,).,excretion of phosphate,excretion of H,+,(more acidic environment favors demineralization of bone),ALSO,Stimulates transcription of 1-alpha hydroxylase for Vitamin D activation in kidney,the active metabolite of,vitamin D3,(required for calcium absorption from the small intestine,bone demineralization).,NET RESULT,:increased plasma calcium levels,26,27,Regulation of PTH Secretion,PTH is released in response to changes in plasma,calcium levels,(negative feedback).,PTH cells contain a receptor for calcium,coupled to a G protein.,calcium,Gq PLCIP3 calcium,inflow,，,ER calcium,release PTH,Also,vitamin D,，,Mg,2+,P,，,somatostatin,PTH,28,29,PTH,Calcium&Phosphate,30,Vitamin D,31,32,Vitamin D Metabolism,Effects of Active Form of Vit D3,Promotes intestinal absorption of calcium,promotes bone,mobilization,(stimulate osteoclasts precursor mature and turnover,Ca,2+,Pi,),mainly,promotes bone,deposition,（,stimulate osteoblasts,osteocalcin,other protein,deposition,calcification,）,Has slight effect to increase calcium re-absorption in kidneys,Works with PTH to cause calcium absorption from bone,PTH,33,Proposed Mechanism of Action of 1,25-DihydroxyD,3,in Intestine,34,Regulation of Vitamin D Metabolism,PTH,1-hydroxylase activity,production of active form,PTH,24-hydroxylase t,ranscription,1,24,25,（,OH,）,3,D,3,phosphate,1-hydroxylase activity,Ca,PTH,1,25,（,OH,）,2,D,3,1-hydroxylase activity,1,25,（,OH,）,2,D,3,24-hydroxylase t,ranscription,1,24,25,（,OH,）,3,D,3,Growth hormone,prolactin,estrogen,calcitonin,1,25,（,OH,）,2,D,3,cortisol,1,25,（,OH,）,2,D,3,35,Changes in vitamine D plasma level,Hypovitaminosis,RICKETS(rachitis)children,OSTEOMALACIA-adults,Attention!,Osteoporosis is decrease of bone mass(matrix and minerals),Hypervitaminosis,Tissue and organs calcification,Lost of body weight,Kidney function failur,e,36,Calcitonin,37,Product of parafollicular C cells of the thyroid,32 aa,Calcitonin,38,The target cell for calcitonin is,the osteoclast,.,-Calcitonin acts via increased cAMP concentrations to,inhibit osteoclast motility,and cell shape and inactivates them.,（,15min,70%,，,mainly in children but not in adult,）,-The major effect of calcitonin administration is a rapid fall in Ca,2+,caused by inhibition of bone resorption.,osteoblastic activity,Ca P deposition,（,1h,）,Ca,P,Mg,Na and Cl resorption in kidney tubules,(weak),Actions of Calcitonin,39,40,Comparison of Calcitonin Effects with PTH Effects,(1)PTH-slowly,need several hrs.,CT-rapidly,less than 1 hr.,(2)PTH-long-term regulation,CT-short-term regulation,PS Wang/2004.05,What is the Role of Calcitonin in HumansRemoval of the thyroid gland has no effect on plasma Ca levels!,Excessive calcitonin release does not affect bone metabolism!,Other mechanisms are more important in regulating calcium metabolism(,i.e.,PTH and vitamin D).,41,Calcitonin,Role of calcitonin in normal Ca,2+,control is not understoodmay be more important in,control of bone remodeling.,Used clinically in treatment of,hypercalcelmia,and in certain bone diseases in which sustained reduction of osteoclastic resorption is therapeutically advantageous.,May be more important in regulating bone remodeling than in Ca,2+,homeostasis.,42,Regulation of Calcitonin Release,Calcitonin release is stimulated by,increased circulating plasma calcium,levels.,Calcitonin release is also caused by the gastrointestinal hormones gastrin and cholecystokinin(CCK),whose levels increase during digestion of food.,Food(high calcium),gastrin,CCK,glucagon,secretin,increased,calcitonin,decreased bone,resorption,43,Factors affecting bone turnover,44,Factors affecting bone turnover,Other hormones,Glucocorticoids,gut-decrease absorption,bone-increased re-absorption/decreased formation,Kidney-excretion of both calcium and phosphate,Thyroxine,stimulates formation/resorption,net resorption,Kidney-excretion of calcium,Growth hormone,Stimulate bone formation,renal calcium excretion,gastrointestinal absorption of calcium,Oestrogen,gut-increased absorption,bone-decreased re-absorption,45,Estrogens and Androgens:both stimulate bone formation during childhood and puberty.,Estrogen inhibits PTH-stimulated bone resorption.,Estrogen increases calcitonin levels,Osteoblasts have estrogen receptors,respond to estrogen with bone growth.,Postmenopausal women(low estrogen)have an increased incidence of osteoporosis and bone fractures.,46,47,W.F.Ganong:Review of Medical Physiology 2003 20th Ed.fig.21-6#1441,Factors affecting bone turnover,Local factors,I-LGF 1(somatomedin C),increased osteoblast prolifn,TGF,increased osteoblast activity,IL-1/OAF,increased osteoclast activity(myeloma),PGs,increased bone turnover(#s/inflammn),BMP,bone formation,48,Factors affecting bone turnover,Other factors,Local stresses,Electrical stimuli,Environmental,temp,oxygen levels,acid/base balance,49,Nutrition and Calcium,50,Nutrition and Calcium,Heaney RP,Refferty K Am J.Clin Nutr 2001,74,:343-7,Excess calciuria associated with consumption of,carbonated beverages,is confined to caffeinated beverages.,Acidulant type(phosphoric vs.citric acid)has no acute effect.,The skeletal effects of carbonated beverage consumption are due primarily to milk displacement.,51,Nutrition and Calcium,See Nutrition 2000 Vol 16(7/8)in particular:,Calvo MS“Dietary considerations to prevent loss of bone and renal function”,“,overall trend in food consumption in the US is to drink,less milk and more carbonated soft drinks,.”,“High phosphorus intake relative to low calcium intake”,Changes in calcium homeostasis and PTH regulation that promote bone loss in children and post-menopausal women.,High sodium associated with fast-food consumption competes for renal reabsorption of calcium and PTH secretion.,52,Nutrition and Calcium,See Nutrition 2000 Vol 16(7/8)in particular:,Harland BF“Caffeine and Nutrition”,Caffeine,is most popular drug consumed world-wide.,75%comes from coffee,Deleterious effects associated with,pregnancy and osteoporosis.,Low birth-rate and spontaneous abortion with excessive consumption,For every 6 oz cup of coffee consumed there was a net loss of 4.6 mg of calcium,However,if you add milk to your coffee,you can replace the calcium that is lost.,53,Effects of soft drinks,Intake of carbonated beverages has been associated with,increased excretion and loss of calcium,25 years ago teenagers drank twice as much milk as soda pop.Today they drink more than twice as much soda pop as milk.,Another significant consideration is obesity and increased risk for diabetes.,For complete consideration of ill effects of soft drinks on health and environment see:,sodium intake,Excessive intake of Na may cause renal hypercalciuria by impairing Ca reabsorption resulting in compensatory increase in PTH secretion.,Stimulation of intestinal Ca absorption by PTH-induced 1,25-(OH)2-D production compensates for excessive Ca excretion,Post-menopausal women at greater risk for bone loss due to excessive Na intake due to impaired vitamin D synthesis which accompanies estrogen deficiency.,55,Effects of Exercise,Bone cells respond to pressure gradients in laying down bone.,Lack of weight-bearing exercise decreases bone formation,while increased exercise helps form bone.,Increased bone resorption during immobilization may result in hypercalcemia,56,Exercise and Calcium,Normal bone function requires weight-bearing exercise,Total,bed-rest causes bone loss and negative calcium balance,57,58,3.Disorders of calcium metabolism and,metabolic bone disease,59,Hypercalcaemia,60,physiological response of hypercalcaemia,plasma calcium,PTH,bone,：,breakdown of bone;formation of bone,gut,：,formation of calcitrol,less Ca,2+,uptake from gut,kidney,：,Ca,2+,absorption,excess Ca,2+,lost in urine,plasma calcium,61,Causes of Hypercalcemia,Common,Uncommon,Malignant disease,e.g.some lung cancers,Renal failure,Hyperparathyroidism,Sarcoidosis,Vitamin D toxicity(excessive intake),Multiple myeloma,62,PTHrP;Parathyroid Hormone related Protein,It is synthesized as 3 isoforms as a result of alternative splicing(139,141,173 aa),Can activate the PTH receptor,Plays a physiological role in lactation,possibly as a hormone for the mobilization and/or transfer of calcium to the milk,May be important in fetal development,May play a role in the development of hypercalcemia of malignancy,Some lung cancers are associated with hypercalcemia,Other cancers can be associated with hypercalcemia,63,PTHrP;Parathyroid Related Protein,64,Symptoms:,They are classically summarized by the mnemonic,stones,bones,abdominal groans and psychic moans”,Stones,refers to,kidney stones,nephrocalcinosis,and,diabetes insipidus(,polyuria and polydipsia,).,Bones,refers to bone-related complications,osteitis fibrosa cystica,which results in pain and sometimes pathological fractures,osteoporosis,osteomalacia,and arthritis.,“Abdominal Groans”,refers to gastric related symptoms such as,Abdominal pain,vomiting,constipation and anorexia,.,Psychic moans”,which includes,depression,memory loss,psychosis,ataxia,delirium,and coma.,65,66,67,Left:Giant Cell Granuloma,Right:Loss of lamina dura,pathognomonic oral change in hyperparathyroidism,68,Signs,Proximal muscle weakness,Signs of Dehydration,Altered mental state.,69,Investigations:,Serum calcium and phosphate,:,phosphate is low in primary hyperparathyroidism and some cases of malignancy,normal or inappropriately high in other causes of hypercalceamia.,PTH level,:,high in hyperparathyroidism.,Radiology,(lytic lesions,subperiosteal erosions in the phalanges).,70,Investigation,If PTH is undetectable the following tests should be done:,-,protein electrophoresis,for myeloma.,-TSH,to exclude hyperthyroidism.,-,synacthen test,to exclude Addisons disease.,-,hydrocortisone suppression test,+ve in sarcoidosis,vitamin D-mediated hypercalceamia and some maligna