Download 内分泌学―――Lecture Note

钙磷代谢的调节
1. 总介：三种重要“激素”
• Calcium is fundamentally important to all biological systems
• Calcium concentration [Ca2+] in cellular and extracellular fluids remains relatively
constant in spite of marked variations in intake and excretion
• Hormonal control: PTH, vitamin D, calcitonin
• Major regulatory organs: intestine, bone, kidneys
2. 维持细胞外钙离子浓度的意义
• Muscle contraction & relaxation
• Nerve conduction
• Blood clotting
• Bone and teeth formation
• Secretory activity of endocrine & exocrine cells
• Second messenger
3. 调节钙磷代谢的器官
Major organs: GI, Skeleton, Kidney
Facilitatory organs: Skin, Liver
• GI tract
1. GI tract is the interface between Ca metabolism and the external environment
2. Ca is absorbed by passive diffusion and active transport. Active absorption is stimulated by
1,25-(OH)2-D
3. Ca enters ECF and into equilibrium with intracellular fluid, glomerular filtrate, and bone fluid
4. Absorption increases during growth, pregnancy and lactation; Ca loss occurs during pregnancy
and lactation
• Kidneys
1. 90% of Ca reabsorbed by renal tubules
2. PTH increases Ca reabsorption
• Skeleton
1. Contains over 99% of body Ca
2. Provides mechanical strength to the bones
3. Serves as a reservoir for maintaining plasma Ca homeostasis
4. Vitamin D
• Vitamin D, after its activation to the hormone 1,25-(OH)2-D, is one of the two major regulators
of Ca & PO4 metabolism
• Sources of vitamin D:
- produced in the skin by UV radiation (D3)
- ingested in the diet (D3 rich in fish, liver, milk; D2 rich in vegetables)
Vitamin D is not a “classic hormone” because it is not produced by an endocrine gland. However,
its metabolite acts as a hormone by the mechanism similar to that of thyroid and steroid hormones
A. VD 合成
• Summer sunlight (290-315 nm) stimulates skin cell to produce previtamin D3 which is then
converted to vitamin D3
• Over exposure to sunlight converts previtamin D3 to inactive products
• Vitamin D has very little intrinsic biological activity and must undergo successive
hydroxylations in order to act as a hormone
• In liver, it is hydroxylated to 25-OH-D which is transported to kidney to form 1,25- (OH)2-D or
24,25-(OH)-D
• 1,25- (OH)2-D is the most potent vitamin D metabolite
• Biological activity of 24,25-(OH)-D is unclear
B. VD 代谢
• All forms circle bound to α-globulin
• 1,25-(OH)2-D has the shortest half-life and the lowest concentration
• [1,25-(OH)2-D] is independent of [25-(OH)-D] except severe vitamin D deficiency
• [24,25-(OH)2-D] is directly proportional to [25-(OH)-D]
C. 1,25-(OH)2-VD 作用
• Acts through nuclear receptors
1). Intestine:
• increases Ca absorption
� increases synthesis of Ca pump, Ca channel, calbindin
� increases active absorption in the duodenum
• stimulates phosphate absorption
2). Bone:
• stimulates Ca and PO4 resorption
• provides Ca and PO4 from old bone to mineralize new bone
3). Kidney:
• targets on distal tubule
• enhances Ca and PO4 reabsorption
Calbindins
• A family of calcium-binding proteins
• Concentrations rise hours after Ca entry from intestinal lumen
• Ferry Ca across the intestinal cell and buffer the high Ca concentration
5. 甲状旁腺
• 4 glands located behind the thyroid
• each gland weighs 30-50 mg
• main cell type: chief cells; present throughout life
影响甲状旁腺分泌的因素
• Ca & PTH form a negative feedback pair
• 1,25-(OH)2-D & PTH form negative feedback loop
• Mg: chronic hypomagnesium inhibits PTH synthesis and impairs response of target tissues to
PTH
• PO4 ↑ → Ca ↓ → PTH ↑
• PTH secretion is pulsatile. Secretion increases at night and with aging. The nocturnal peak is
independent of the plasma calcium concentration.
甲状旁腺素的功能
• PTH effects are mediated through cAMP mechanism
• Major target organs
- bone (direct effect)
- Kidney (direct effect)
- GI tract (indirect effect)
• Overall effect
- increase plasma [Ca2+]
- decrease plasma [PO4]
1). PTH Action on Bone
• Osteoblasts have PTH receptors
• PTH acts on osteoblasts to increase number/activity of osteoclasts and releases Ca & PO4
• PTH acting collaboratively with 1,25(OH)2-D activates osteoblasts to stimulate formation of
new bone
• Anabolic actions of PTH are favored by normal blood levels of PTH
• High concentrations elicit catabolic changes which overwhelm the anabolic effect, as seen in
hyperparathyroidism where bone resorption predominates
2) PTH Action on Kidney
• Increases reabsorption of Ca from thick ascending limb and distal tubule
• Inhibits reabsorption of PO4 from proximal tubule → prevents precipitation
• Stimulates the synthesis of 1,25-(OH)2-D
6. 降钙素
合成及其调节
• Produced by C cells of thyroid gland
• ↑[Ca] → ↑calcitonin
• Food ingestion increases calcitonin secretion without increasing plasma Ca concentration
• Gene directs synthesis of
- calcitonin
- Calcitonin gene-related peptide (CGRP): vasodilator
降钙素的功能
• Major target cell – osteoclast (has calcitonin receptor)
- cAMP mechanism
- inhibits synthesis and activity of osteoclasts → ↓ bone turn over
- transitory action (“escape”) due to down-regulation of its receptors
• Effect on Ca: Antagonist to PTH (↓ plasma Ca)
• Effect on PO4: same as PTH (↓ plasma PO4)
• Renal effect
- mild phosphaturia
- mild calciuresis
• Contribute to fetal skeletal development
• Plasma calcitonin is lower in women than in men & declines with aging
• Calcitonin is used in
- acute treatment of hypercalcemia
- alternative of estrogen for treating osteoporosis in women
- treat Paget disease (localized regions of bone resorption & reactive sclerosis)
7. 低钙、高钙血症、佝偻病
Blood Ca too high - Hypercalcemia: sluggish nervous system, possible cardiac arrest
Blood Ca too low - TETANY: Inability for muscles to relax (muscles tremor i.e carpopedal
spasms and laryngospasms….shuts off air… and can cause suffocation
Rickets: Deficiency of vitamin D (dietary deficiency, insufficient sun exposure, liver/kidney
diseases) causes inadequate mineralization of new bone matrix (lowered ratio of mineral/organic
matrix)
Symptoms: decreased mechanical strength and distortion especially in the long bones of legs
The specific radiographic features:
- the failure of cartilage calcification and endochondral ossification (best seen in the metaphysis of
rapidly growing bones)
- the metaphyses are widened, uneven, concave, or cupped and because of the delay in or absence
of calcification, the metaphyses could become partially or totally invisible.