LECTURE 5 (Parathyroid) Flashcards
How is calcium present in the body?
- combined with plasma proteins (non-diffusible through the capillary membrane)
- combined with anionic substances of plasma and interstitial fluids [IONISED] (diffusible through capillary membrane)
- diffusible through capillary membrane AND ionised
Which forms does inorganic phosphate exist in the plasma?
- HPO4+
- H2PO4-
Explanation: When the total quantity of phosphate in the extracellular fluid rises, so does the the quantity of each type of phosphate
What happens when the pH of the extracellular fluid becomes more acidic?
A relative increase in H2PO4- and a decrease in HPO4+
Explanation: This is to react with the increase in H+ in order to maintain the acid-base balance. The opposite occurs when the ECF becomes too alkaline.
What happens in Hypocalcemia?
ECF concentration of calcium ions falls below normal -> nervous system becomes progressively more excitable since it causes increased neuronal membrane permeability to Na+ -> allows for easy initiation of action potentials
MANIFESTATIONS:
- Tetany
- Carpopedal spasm (tetany in the hand)
- Dilation of heart
- Increased membrane permeability in some cells
- Impaired blood clotting
What happens in Hypercalcemia?
Calcium in ECF rises above normal -> nervous system becomes depressed and reflex activities of the CNS are sluggish -> increased Ca2+ concentration decreases the QT interval of the heart and causes lack of appetite and constipation (due to depressed contractility of the GI muscle walls)
What does Vitamin D promote?
calcium absorption by the intestines
Describe the organic matrix of bone
- 90-95% collagen fibers (extend along lines of tensional force + give bone its powerful tensile strength)
- ground substance (ECF, proteoglycans- chondroitin sulphate + hyaluronic acid)
- bone salts (calcium + phosphate) “hydroxyapatite”
______________ inhibits the precipitation of hydroxyapatite crystals in normal tissues except for bone despite supersaturation of the ions
Pyrophosphate
Describe the process of bone calcification
1) Osteoblasts secrete collagen molecules and ground substance and the collagen monomers POLYMERISE rapidly to form collagen fibers forming an OSTEOID (a cartilage-like material differing from cartilage in that Ca2+ salts readily precipitate in it)
2) Some osteoblasts become entrapped in osteoid and become quiescent and become OSTEOCYTES
3) Calcium salts begin to precipitate on the surfaces of collagen fibers and rapidly multiply to form HYDROXYAPATITE CRYSTALS
Where do calcium salts precipitate under abnormal conditions?
- Arterial walls (forming arteriosclerosis)
- Degenerating tissues
- Old blood clots
What is the importance of exchangeable calcium?
It provides a rapid buffering mechanism to keep calcium ion concentration in the ECF from rising to excessive levels or falling to low levels under transient conditions of excess or decreased availability of calcium
What are osteoclasts?
Large, phagocytic, multinucleated cells that are derivatives of monocytes or monocyte-like cells in the bone marrow that absorb bone
Describe the process of bone absorption
1) Osteoclasts send out villus-like projections towards the bone, forming a ruffled border adjacent to the bone
2) The villi secrete PROTEOLYTIC ENZYMES (released from lysosomes of osteoclasts) and SEVERAL ACIDS (like citric acid and lactic acid released from the mitochondria and secretory vesicles) -> enzymes digest or dissolve organic matrix of bone and acids cause dissolution of bone salts
3) Osteoclastic cells also phagocytose minute particles of bone matrix and crystals, dissolving these and releasing the products into the blood
How does parathyroid hormone (PTH) stimulate osteoclast activity and bone resorption?
1) PTH binds to receptors on adjacent osteoblasts causing them to release cytokines including OSTEOPROTEGERIN LIGAND/RANK LIGAND
2) OPGL activates receptors on preosteoclast cells causing them to differentiate into mature multinucleated osteoclasts
3) Mature osteoclasts develop a ruffled border and release enzymes and acids that promote bone resorption
What is Osteoprotegerin?
Osteoprotegerin (OPG), also called “osteoclastogenesis inhibitory factor”, is secreted by osteoblasts and prevents OPGL from interacting with its receptor which inhibits differentiation of proteoclasts into mature osteoclasts that resorb bone
What is important about bone deposition and absorption?
The rates of bone deposition and absorption are equal to each other so the total mass of bone remains constant
Describe the process of bone remodelling
1) Osteoclasts eat away the bone and create a tunnel. Once the osteoclasts disappear, the tunnel is invaded by osteoblasts and new bone begins to develop.
2) New bone being laid down in successive layers of concentric circles (lamellae) on the inner surfaces of the cavity until the tunnel is filled
3) Deposition of new bone stops when the bone begins to grow blood vessels to supply the area (canal is called the HAVERSIAN CANAL)
What is the importance of bone remodelling?
- bones ordinarily adjust its strength in proportion to the degree of bone stress (bones thicken when subjected to heavy loads)
- shape of bone can be rearranged for proper support
- old becomes become brittle and weak (new bone is needed when old bone degenerates)
What does “bone stress” cause?
- stimulates osteoblastic deposition and calcification of bone
- determines shape of bones
Describe the activation of Vitamin D3 to form 1,25-dihydroxycholecalciferol
1) Vitamin D3 (CHOLECALCIFEROL) is formed in the skin as a result of irradiation of 7-DEHYDROCHOLESTEROL (from UV rays)
2) Vitamin D3 is converted in the liver into 25-HYDROXYCHOLECALCIFEROL (limited since has an inhibitory feedback to be converted back to Vitamin D3 to be stored in liver for months)
3) 25-HYDROXYCHOLECALCIFEROL is converted to 1,25-DIHYDROXYCHOLECALCIFEROL in the kidneys in the presence of PTH (absence of kidneys or PTH -> cannot happen)
What is the importance of the inhibitory feedback mechanism of Vitamin D3 to 25-hydroxycholecalciferol?
- It regulates the concentration of 25-hydroxycholecalciferol in the plasma (high degree of feedback control prevents excessive action of vitamin D when intake is high)
- Conserves the vitamin D stored in liver for future use (25-hydroxycholecalciferol lasts for several weeks but vitamin D in the liver can stay for months)
What is the effect of Ca2+ concentration on the formation of 1,25-dihydroxycholecalciferol?
- Ca2+ ion prevents conversion of 25-hydroxycholecalciferol to 1-25,dihydroxycholecalciferol
- At higher Ca2+ concentrations, PTH is suppressed and the 25-hydroxycholecalciferol is converted to 24,25-DIHYDROXYCHOLECALCIFEROL (no vitamin D effect)
[explanation: when plasma Ca2+ concentration is too high, formation of 1,25-dihydroxycholecalciferol is greatly depressed -> decreases absorption of Ca2+ from intestines, bones, renal tubules -> Ca2+ concentration falls back towards normal level]
Describe Vitamin D receptors
- located in nuclei of target cells
- hormone-binding and DNA-binding domains
- forms a complex with retinoid-X-receptor which binds to DNA to activate transcription
How does 1,25-dihydroxycholecalciferol promote calcium absorption in the intestines?
- Over a period of 2 days, increases formation of CALBINDIN (calcium-binding protein) in intestinal epithelial cells which functions to transport Ca2+ into the cell cytoplasm -> Ca2+ moves through basolateral membrane by FACILITATED DIFFUSION -> protein remains in cells for weeks after 1,25-dihydroxycholecalciferol has been removed (has a prolonged effect on Ca2+ absorption)
[rate of absorption is directly proportional to quantity of calcium-binding protein] - Formation of a calcium-stimulated ATP-ase in brush border of epithelial cells
- Formation of alkaline phosphatase in epithelial cells
What are the other effects of Vitamin D other than Ca2+ absorption?
- Increases phosphate absorption by intestines
- Increases Calcium and Phosphate reabsorption by epithelial cells of renal tubules (decrease excretion in urine)
- Extreme quantities of Vitamin D -> absorption of bone
- Vitamin D in smaller quantities -> promotes bone calcification
[caused by ability of 1,25-dihydroxycholecalciferol to transport Ca2+ through cell membranes]
Describe the anatomy of the Parathyroid glands
- Four parathyroid glands located behind the thyroid gland
- Removal of 3 or 4 parathyroid glands causes hypoparathyroidism [small quantity of parathyroid tissue can hypertrophy to keep doing function]
- Chief cells = secrete PTH
- Oxyphil cells = do not secrete hormone
Describe the formation of Parathyroid hormone (PTH)
First synthesised as “preprohormone” on the ribosomes -> cleaved to “prohormone” -> cleaved to “parathyroid hormone” by endoplasmic reticulum and Golgi apparatus and packaged into secretory granules in the cytoplasm of cells
What is the effect of parathyroid hormone on Calcium and Phosphate ECF concentrations?
- Increased calcium and phosphate absorption from bone
- Decreased excretion of calcium by the kidneys + increased excretion of phosphate by kidneys
[explains why phosphate concentration falls more rapidly than calcium]
What are the two phases that PTH causes absorption of calcium and phosphate in bone?
- RAPID PHASE = activation of already existing bone cells, mainly osteocytes (within minutes)
- SLOW PHASE = proliferation of osteoclasts followed by increased reabsorption of bone itself, not just calcium phosphate salts from bone (several days/weeks)
Describe the rapid phase of calcium and phosphate absorption from bone (OSTEOLYSIS)
- PTH causes removal of bone salts from bone matrix near osteocytes within the bone and near osteoblasts along the bone surface
- Osteocytes and osteoblasts create a OSTEOCYTIC MEMBRANE SYSTEM which is separated from ECF by “bone fluid” -> OMS pumps Ca2+ from bone into ECF -> When pump is inactivated, bone fluid calcium concentration rises and calcium phosphate salts are brought back to matrix
- PTH activates Ca2+ pump strongly [increases Ca2+ permeability allowing Ca2+ to diffuse into membrane cells + transfers Ca2+ into ECF]
Describe the slow phase of bone absorption and calcium phosphate release
- Osteoclasts do not have membrane receptor proteins for PTH -> activated osteoblasts + osteocytes send “secondary signals” to osteoclasts (e.g osteoprotegerin ligand)
- Activation of osteoclastic system causes: immediate activation of already formed osteoclasts + formation of new osteoclasts
- Prolonged administration/secretion of PTH can lead to weakened bones
What causes parathyroid glands to hypertrophy/enlarge?
- Rickets/Osteomalacia
- Pregnancy
- Lactation (Ca2+ to form milk)
Explanation: even the slightest decrease in Ca2+ concentration in the ECF causes parathyroid glands to increase their rate of secretion + hypertrophy
What causes parathyroid glands to reduce in size?
- Excess quantities of Ca2+ in diet
- Increased vitamin D intake
- Bone absorption caused by factors other than PTH
Explanation: conditions that increase Ca2+ concentration above normal cause decreased activity and size of parathyroid glands
Describe the control of Parathyroid secretion by Calcium ion concentration
1) Changes in ECF Ca2+ concentration are detected by CALCIUM-SENSING RECEPTOR (CaSR) in parathyroid cell membranes
[CaSR is a G protein, when stimulated by Ca2+ activates phospholipase C and increases intracellular inositol 1,4,5-triphosphate and diacylglycerol formation]
2) CaSR stimulation releases Ca2+ from intracellular stores which decreases PTH secretion
or
decreased ECF Ca2+ concentration inhibits these pathways and stimulates PTH secretion
What is the overall effect of Parathyroid hormone?
- Stimulates bone resorption, causing release of Ca2+ into ECF
- Increases reabsorption of Ca2+ and decreases phosphate reabsorption by renal tubules -> decreased excretion of calcium + increased excretion of phosphate
- Conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol -> increases Ca2+ absorption by intestines
What is Calcitonin?
A peptide hormone secreted by the thyroid gland that tends to decrease plasma calcium concentration. Synthesis and secretion occur in PARAFOLLICULAR CELLS or C CELLS in the interstitial fluid between the follicles of the thyroid gland.
Explanation: Stimulus for calcitonin secretion is increased ECF Ca2+ concentration [causes decreased osteoblast + osteoclast activity but effect is not as potent compared to PTH]
What is the first line in defence before PTH and Calcitonin action?
Amorphous calcium phosphate compounds are in reversible equilibrium with calcium and phosphate ions in the ECF of bone
What is Hypoparathyroidism?
When the parathyroid glands do no secrete sufficient PTH leading to decreased osteocytic resorption of calcium which causes levels of calcium in body fluid to decrease
MANIFESTATIONS:
- Tetany
- Tetany in laryngeal muscles -> respiration obstruction -> death
TREATMENT:
- PTH (not usually used as expensive + tendency of antibodies to develop against it)
- Administration of Vitamin D/1,25-dihydroxycholecalciferol
- Administration of Ca2+
What is Primary Hyperthyroidism?
An abnormality of the parathyroid glands that causes inappropriate, excess PTH secretion (usually a tumour) which causes extreme osteoclastic activity in the bones
MANIFESTATIONS:
- Osteitis fibrosa cystica = fractures of weakened bones from slight trauma where cysts develop
- Weakened bones
- Depression of CNS and PNS: muscle weakness, constipation, abdominal pain, peptic ulcer, lack of appetite and depressed relaxation of heart
- Calcium phosphate crystals form in alveoli of lungs, kidney tubules, thyroid glands, acid-producing area of stomach mucosa and walls of arteries
- Parathyroid poisoning
- Kidney stones
LAB FINDINGS:
- High levels of plasma alkaline phosphatase (osteoblasts compensate and release lots of alkaline phosphatase)
What is Secondary hyperparathyroidism?
High levels of PTH occur as a compensation of hypocalcemia. It is caused by Vitamin D deficiency or chronic renal disease (damaged kidneys are unable to form 1,25-dihydroxycholecalciferol.
What is Rickets?
Occurring mainly in children, results from calcium or phosphate deficiency in ECF caused by lack of Vitamin D
MANIFESTATIONS:
- Plasma Ca2+ is only slightly depressed but plasma phosphate is greatly depressed (parathyroid gland have a feedback mechanism for calcium but increase excretion of phosphates in urine)
- Weakened bones (increased osteoclast activity + uncalcified, weak osteoid replaces older bone)
- Tetany
What is Osteomalacia “adult rickets” caused by?
Usually not dietary deficiency of vitamin D, since large quantities are not needed for bone growth compared to children, but Steatorrhea (excessive fat in poop, vitamin D and calcium escape into poop)
What is Renal rickets?
A type of Osteomalacia caused by prolonged kidney damage. The damaged kidneys fail to form 1,25-dihydroxycholecalciferol, an active form of Vitamin D.
What is Congenial hypophosphatemia?
It results from congenitally reduced reabsorption of phosphates by renal tubules and must be treated with phosphate compounds instead of calcium and vitamin D, called “Vitamin D-resistant rickets”
What is Osteoporosis?
A bone disease in adults that results from diminished organic bone matrix. The osteoblastic activity in the bone is less than normal and the rate of bone osteoid deposition is depressed.
CAUSES:
- Lack of physical stress on bones due to inactivity
- Malnutrition
- Lack of Vitamin C (needed to form osteoid by osteoblasts)
- Postmenopausal lack of oestrogen (it decreases number + activity of osteoclasts)
- Old age
- Cushing’s syndrome (increased catabolism of protein + depresses osteoblastic activity)
What is Enamel?
- Outer surface of tooth formed before eruption of tooth by AMELOBLASTS
[once tooth has erupted, no more enamel is formed] - Composed of large and dense crystals of hydroxyapatite and other ions embedded in a meshwork of strong + insoluble protein fibers
- Crystalline structure makes it really hard
What is Dentin?
- Composes main body of tooth
- Made up of hydroxyapatite crystals + meshwork of collagen fibers -> really strong
- Deposited and nourished by ODONTOBLASTS which line inner surface
- Ca2+ salts make it resistant to compressional forces + collagen fibers to tensional forces
What is Cementum?
- Bony structure secreted by cells of the PERIODONTAL MEMBRANE which lines tooth socket
- Collagen + Cementum hold tooth in place
- Gets thicker and stronger with excessive strain and age
What is Pulp?
- Composed of connective tissue with nerve fibers, blood vessels and lymphatics
- ODONTOBLASTS line pulp cavity which make it smaller overtime
How many “milk teeth” and “adult teeth” do humans have?
20 deciduous teeth “milk teeth” and 28-32 adult teeth, depending if all four wisdom teeth appear
Describe the formation of teeth
1) Invagination of oral epithelium into DENTAL LAMINA followed by tooth-producing organ
2) Epithelial cells above form AMELOBLASTS which form enamel on outside of tooth
3) Epithelial cells below invaginate upward into middle of tooth to form pulp cavity and ODONTOBLASTS that secrete dentin
What is Caries/Cavities?
Generally caused by bacteria on teeth, is the erosion of teeth.
CAUSE:
plaque (palm of precipitated saliva and food) on teeth -> bacteria use these carbohydrates to multiply -> produce acids and proteolytic enzymes which dissolve calcium salts
PREVENTION:
- Fluorine ions replace many hydroxyl ions in hydroxyapatite crystals making enamel less soluble
- Fluorine is toxic to bacteria
- Fluorine promotes healing of enamel surface
What is Malocclusion?
Usually caused by a hereditary abnormality that causes the teeth of one jaw to grow to abnormal positions.
MANIFESTATIONS:
- teeth do not integrate properly -> cannot perform normal grinding or cutting action adequately
