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肾性骨病与钙磷代谢紊乱精要课件

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肾性骨病 代谢 紊乱 精要 课件
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Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 肾性骨病与钙磷代谢紊乱肾性骨病与钙磷代谢紊乱 安徽医科大学第一附属医院安徽医科大学第一附属医院 肾内科肾内科 张伯科张伯科 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 人体所需的营养素中包括部分无机 盐 以金属离子为主的多种离子在酶促 反应过程中发挥作用 而钠 钾 氯等 离子在维护渗透压过程中起重要作用 钙磷是骨骼的重要组成成分 在信息传 递 凝血等过程中无机离子亦有重要作 用 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 一 人体内钙 磷的分布 及生理功能 人体钙和磷含量 钙约占体重1 5 2 2 总量 约为700 1400g 磷占体重0 8 1 2 总量约 400 800g Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 存在形式 99 的钙和86 的磷以羟磷灰石的 形式存在于骨和牙齿当中 其余分布于体液和软组织中 以溶 解状态存在 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 人体内钙的存在状态 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 钙磷代谢概貌 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 血钙和血磷 血钙 血浆中所含的钙 正常成人血 钙为 2 45mmol L 分为 可扩散钙 diffusible calcium 非扩散钙 nondiffusible calcium Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 非扩散钙 指与血浆蛋白 主要为白蛋白 结合的钙 不易透过毛细血管壁 可扩散钙 主要为游离 Ca2 及少量与柠檬酸或其 它酸结合的可溶性钙盐 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 血浆中发挥生理作用的主要 为游离Ca2 而血浆中Ca2 蛋白结合钙和小分子游离钙之间 呈动态平衡关系 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 此平衡受血浆PH影响 血液偏酸时 游离Ca2 浓度 血液偏碱时 蛋白结合钙 游离Ca2 浓度 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 血磷 血浆中的磷以无机磷盐的形 式存在 正常人血磷的浓度为 1 2mmol L 血磷不如血钙稳定 可受生 理因素影响而变动 如糖代谢 增强时 血中无机磷进入细胞 使无机磷下降 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 血浆中钙 磷浓度关系 Ca P 30 40mg dl Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 当 Ca P 40 则钙和磷以骨盐形 式沉积于骨组织 若 Ca P 空肠 回肠 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 吸收机理 跨膜转运 细胞内转运 主动吸收 被动扩散 易化转运 钙结合蛋白 calcium binding protein 与Ca2 有较强亲和力 可促 进钙的吸收 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 磷的吸收 肠道主要吸收无机磷 有机含磷物则 经水解释放出无机磷而被吸收 吸收部位 遍及小肠 以空肠吸收率 最高 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 钙和磷的排泄 钙主要经两条途径排泄 肾排出 约20 肾小球每日滤出钙约 10g 95 以上被肾小管重吸收 0 5 5 随尿排出 粪便排出 约20 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 磷主要有两条途径 肾脏排泄 以肾脏排泄为主 尿磷排 出量占总排出量的60 80 尿磷排 出量取决于肾小球滤过率和肾小管重 吸收功能 并随肠道摄入量的变化而 变化 肠道排出 占总排出量的20 40 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 三 钙 磷的生理作用 钙的生理作用 1 第二信使的作用 受体 激素 因子 磷脂酶C PIP2 IP3 DAG 内质网释放Ca2 第二信使 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 成骨作用 骨是一种特殊的结缔组织 不仅作为 人体的支架组织 而且是人体中钙 磷的 最大储库 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 骨的组成 骨由无机盐又称骨盐 bony salts 有机基质和骨细胞等组成 骨盐增加 骨的硬度 基质决定骨的形状及韧性 骨细胞在代谢中起主导作用 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 骨盐 占骨干重的65 70 主要成分为磷酸钙 占84 其它还有 碳酸钙 柠檬酸钙 磷酸镁 磷酸氢钠等 骨盐约有60 以结晶的羟磷灰石形式存在 其余40 为无定形的磷酸氢钙 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 羟磷灰石 Ca10 PO4 6 OH 2 是微细的结晶 亦称骨晶 bone crystal 每克骨盐含有约1016个结晶 总的表面积可达100m2 体液中其他离子 如Ca2 Mg2 Na Cl HCO 3 柠 檬酸根等可吸附在羟磷灰石的晶格之间 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 骨基质 胶原和非胶原化合物 胶原约占90 以上 非胶原蛋白中 含量较多的是骨钙素 osteocalcin 和 骨连接素 osteonectin Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 成骨作用与钙化 骨的生长 修复或重建过程 称为成骨 作用 osteogenesis Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 成骨细胞先合成胶原和糖白多糖等细 胞间质成分 形成所谓 骨样质 osteoid 继后骨盐沉积于骨样质中 此过程称为钙化 calcification 成骨过程 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 骨的钙化 是一个复杂的过程 磷酸钙盐沉积于 胶原纤维表面 然后随钙沉积增加转变 为羟磷灰石的结晶 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 骨基质中的骨连接素可促进羟磷灰石 结晶的形成 碱性磷酸酶水解磷酸酯类 包括能抑 制骨钙化的焦磷酸盐 使局部磷酸盐 浓度增加 有利于成骨作用 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 溶骨作用与脱钙 骨在不断的新旧更替之中 原有旧骨 的溶解和消失称为骨的吸收 bone resorption 或溶骨作用 osteolysis Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 溶骨作用 包括基质的水解和骨盐 的溶解 后者又称为脱钙 decalcification 溶骨作用主要由破骨 细胞引起 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 破骨细胞的作用 通过细胞内溶酶体释放出多种水解酶类 如胶 原酶可水解胶原纤维 糖苷酶水解氨基多糖 通过糖元分解代谢产生大量乳酸 丙酮酸等酸 性物质扩散到溶骨区 使局部酸性增加 促使 羟磷灰石从解聚的胶原中释出 分解产物经胞饮作用进入破骨细胞 经溶酶体 酶类作用最终将肽水解为氨基酸 羟磷灰石转 变为可溶性钙盐 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 正常成人 成骨与溶骨作用维持动态 平衡 每年骨的更新率约1 4 骨骼 发育生长时期 成骨作用大于溶骨作用 而老年人则骨的吸收明显大于骨的生 成 骨质减少而易发生骨质疏松症 osteoporosis Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 骨盐在骨中沉积或释放 直接影响 血钙 血磷水平 在平时骨中约有1 的 骨盐与血中的钙经常进行交换维持平衡 因此血钙浓度与骨代谢密切相关 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 磷的生理作用 与钙共同构成骨盐参与成骨作用 是核酸 磷酸 高能磷酸化合物 及辅酶的重要组成成分 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 四 钙磷代谢的调节 体内钙 磷代谢的平衡主要由甲状旁 腺素 1 25 OH 2D3和降钙素来调节 一 甲状旁腺素 parathormone PTH 甲状旁腺素是由甲状旁腺主细胞合成 和分泌的一种单链多肽激素 成熟PTH含 84个氨基酸残基 分子量约为9500 是 维持血钙恒定的主要激素 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial PTH作用的靶器官是肾脏 骨骼和小肠 PTH作用于靶细胞膜上腺苷酸环化酶系 统 增加胞浆内cAMP及焦磷酸盐 ppi 的 水平 1 对骨的作用 具有促进成骨和溶骨的双重 作用 PTH可刺激骨细胞分泌胰岛素样 生长因子I 从而促进骨胶原和基质的合 成 利于成骨作用 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 另一方面PTH能使骨组织中破骨细胞 的数量和活性增加 破骨细胞分泌各种 水解酶 并且产生大量乳酸和柠檬酸等 酸性物质 使骨基质及骨盐溶解 释放 钙和磷到细胞外液 但PTH只引起血钙升 高 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 2 对肾脏的作用 主要是增加肾远曲小管对ca2 的重吸 收 降低肾磷排泄阈并抑制肾小管对磷 的重吸收 最终使血钙升高 血磷降低 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 二 1 25 OH 2D3 1 25 OH 2D3是一种激素 由维生素 D3在体内代谢生成 是维生素D3在体内的 主要生理活性形式 维生素D3及其前体在 皮肤 肝 肾等经过一系列的酶促反应 生成1 25 OH 2D3 再经血液运输到小 肠 骨及肾等靶器官发挥生理作用 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 1 25 OH 2D3的生理作用 对小肠的作用 1 25 OH 2D3能促进小肠对钙 磷的 吸收 这是其最主要的生理功能 1 25 OH 2 D3与小肠粘膜细胞内的特异胞浆 受体结合 进入细胞核内 促进DNA转录 生成mRNA 从而使钙结合蛋白 calcium binding protein CaBP和 Ca2 Mg2 ATP酶 合成增高 从而促进ca2 的吸收 转运 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 对骨的作用 1 25 OH 2 D3对骨亦有溶骨和成骨 的双重作用 1 25 OH 2 D3能刺激破骨 细胞活性和加速破骨细胞的生成 从而 促进溶骨作用 另一方面它增加小肠对 钙 磷的吸收 提高血钙 血磷 又促 进钙化 同时它还刺激成骨细胞分泌胶 原等 促进骨的生成 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 对肾的作用 1 25 OH 2 D3可促进肾小管对钙 磷 的重吸收 但此作用较弱 处于次要地 位 1 25 OH 2 D3总的调节效果是使血钙 血磷增高 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 三 降钙素 calcitonin CT 降钙素是由甲状腺滤泡旁细胞 又称c细 胞 所分泌的一种单链多肽类激素 由32个 氨基酸组成 分子量为3500 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial CT作用的靶器官也主要为骨和肾 其作用 与PTH相反 其作用是抑制破骨作用 抑制 钙 磷的重吸收 降低血钙和血磷 目前已发现在骨 肾 肠粘膜 精子等细 胞上有CT受体 CT与受体结合激活腺苷酸 环化酶 通过camp发挥生物效应 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 对骨的作用 CT直接抑制破骨细胞的生成 又可 加速破骨细胞转化为成骨细胞 因而增 强成骨作用 抑制骨盐溶解 降低血钙 血磷浓度 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 对肾的作用 CT直接抑制肾小管对钙 磷离子的重 吸收 从而使尿磷 尿钙排出增多 同 时还可通过抑制肾1 羟化酶而减少1 25 OH 2D3的生成而间接抑制肠道对钙 磷的吸收率 结果使血浆钙 磷水平 下降 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial PTHPTH 1 1 25 25 OH OH 2 2D D3 3 CTCT 血钙血钙 血磷血磷 小肠钙吸收小肠钙吸收 小肠磷吸收小肠磷吸收 肾钙重吸收肾钙重吸收 溶骨作用溶骨作用 成骨作用成骨作用 三种激素对钙 磷代谢的调节 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 五 慢性肾衰竭继发性甲旁亢 定义 流行病学 发病机制 临床表现 实验室检查及影像学检查 治疗 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 基本概念 尿毒症患者肾小球率过滤降低 体内刺激甲 状旁腺的因素 特别是低血钙 低血镁和高血磷 腺体受刺激后增生 肥大 分泌过多的甲状旁 腺激素 代偿性维持血钙 磷正常 随病程进展 PTH促使破骨细胞及成骨细胞增生活跃 形成 新的网织骨 高浓度的血磷又与钙结合沉积于这 些新骨上 这些过度钙化的新骨堆积在干骺端 软骨下及椎体 形成骨分层状硬化和四肢骨骨质 疏松 若iPTH 600 pg ml 大于正常值6倍 称为重度甲旁亢 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 流行病学 在慢性肾衰竭患者 1 多数会发生继发性甲旁亢 但非全部 2 黑人比白人发病率高并更严重 3 糖尿病患者继发性甲旁亢程度较轻 4 血浆25 OH D3水平低的患者PTH水平 高 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 发病机制 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 1 低钙血症及钙受体的下调 2 磷潴留 3 维生素D 及其受体减少 4 靶器官对PTH反应下降 5 甲状旁腺自主性增生 6 PTH 降解改变 7 酸中毒 8 尿毒症毒素等 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 血钙及钙受体 慢性肾衰 1 25 OH 2D3 血Ca2 磷潴留 胃肠道钙吸收 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Ca2 细胞膜钙通道 细胞外钙敏感受体 Ca2 sensing receptor CaR PTH分泌 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial CaR G蛋白偶联细胞表面受体超家族 G protein sensing receptor GPR 血Ca2 CaR 激活 磷酸脂酶C 激活 三磷酸肌醇 IP3 二乙酰甘油 DG 细胞内Ca2 胞内钙动员 胞外钙内流 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial CaR 主要作用 1 介导细胞外钙对PTH分泌的调节 2 参与机体 钙调定点 的设置 调节PTH 合成及组织增生 3 影响肾脏钙的排泄 调节肾脏活性维生素D的合成 介导氨基糖苷类抗生素的肾脏毒性作用 介导高镁血症的病理作用等 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 低钙血症引起血PTH 血Ca2 数分钟内 数小时或数天后 1 PTH释放 2 PTH降解 3 降解片断再利用 PTH mRNA表达 1 PTH基因上游 2315kb 处负性钙反应元件介导 2 转录后调节机制 PTH mRNA 降解 数周或数月后 DNA 复制 细胞分裂 组织增生 PTH 合成增多 释放增加 CaR 细胞内Ca2 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 新近研究发现 1 尿毒症甲状旁腺CaR 基因和蛋白质合成 在结节性增生部位比弥漫性增生部位更明显 2 甲状旁腺中增殖细胞核抗原的表达与CaR 存 在明显负相关 提示CaR 的下调可能参与了甲状 旁腺细胞的增生 并导致细胞外钙变化对PTH 正 常的抑制能力下降 致使PTH 分泌增加 3 磷潴留可能是引起CaR 下调的重要原因 高 磷饮食的尿毒症大鼠甲状旁腺CaR 基因和蛋白表 达显著减少 而低磷饮食可使其完全纠正 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 磷潴留 矫枉失衡 Trade off 学说 1 胃肠道吸收的磷 约1120mg d 90 经肾脏 排泄 约910mg d 2 肾脏病变时极易造成磷潴留 当肾小球滤 过率下降到30ml min 时 从肾排出的磷就 会在体内蓄积引起高磷血症 刺激PTH合成及 释放 3 磷潴留主要通过降低血钙 抑制肾脏活性 维生素D合成 引起骨骼抵抗等途径间接发挥 作用 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 新近研究 血磷升高可直接刺激PTH合成 并参与 甲状旁腺组织的增生 而低血磷具有相反 作用 磷还可以不依赖血钙和1 25 OH 2D3 的作用 直接刺激PTH的分泌 其机制可能 与c fos c jun 和PRAD 1 甲状旁腺腺瘤 1 等原癌基因表达有关 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 甲状旁腺细胞感受细胞外磷 的机制 1 钠磷同向转运体 PiT 1 2 甲状旁腺上磷受体 或磷敏感 分子 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 甲状旁腺细胞有丝分裂 细胞周期蛋白细胞周期素依赖性激酶 cdk 促进 cdk抑制物 如cdk抑制因子p21 抑制 促有丝分裂因素 抗有丝分裂因素 高血磷TGF 限磷 Dusso AS等 2001 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 1 高磷培养液 218mmol L PTH 分泌 6倍于低磷培养液 12mmol L Almaden Y等 1996 2 大鼠 低磷饮食 PTH mRNA结合力 PTH mRNA 降解 大鼠 低钙饮食 PTH mRNA结合力 PTH mRNA稳定性 Moallem E 等 1998 3 尿毒症大鼠 高磷饮食 数天内 甲状旁腺重量 蛋白 DNA 含量 低磷饮食能直接抑制有丝分裂原 从而影响细胞增生 Slatopolsky E等 1999 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 4 尿毒症动物低磷饮食两天 甲状 旁腺细胞细胞周期调节蛋白p21 及其 RNA水平 表明低磷饮食可通过p21 抑制甲状旁腺细胞增生 Dusso A 等 1998 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 磷与钙调控阈值 磷使钙调控阈值上移 血磷越高 PTH 的基础分泌 量和最大分泌量也就越高 Llach F等 1999 3 5 4 0 4 5 5 0 5 5 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 高磷血症 骨骼对 PTH抵抗 低钙血症 1 25 OH 2D3 肠钙吸收 甲旁腺细胞 生长 甲旁腺对 VD3抵抗 PTH分泌 磷潴留引起继发性甲旁亢机制 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial Vit D3及维生素D受体 VDR 肾组织破坏 近曲小管上皮细胞线粒体内的 1 羟化作用 1 25 OH 2D3 生成 钙调控阈值 Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 位于甲状旁腺细胞中的胞浆和胞核上 类固醇 甲状腺超家族核受体 视黄酸X受体 Retinoid X receptor 1 25 OH 2D3受体 VDR 1 25 OH 2D3VDR VDR RXR 异二聚体 RNA聚合酶 介导PTH转录 PTH mRNA 甲状旁腺细胞的增生 Slatopolsky E等 1999 维生素D反应元件 VDRE Five weeks of practice ended in this way and my feelings can only be summed up in eight words although hard but very substantial 活性 VitD 原癌基因 c myc表达周期蛋白激酶抑制剂p21 抑制激活 甲状旁腺细胞增生 抑制 Five weeks of practice ended in this way and my feelings can only be summed up in e
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