Download Physiology Ch 79 p 955-971 [4-25

Physiology Ch 79 p 955-971
Parathyroid Hormone, Calcitonin, Ca and PO4 metabolism, Vitamin D, Bone, Teeth
Overview of Ca and PO4 regulation in extracellular fluid and plasma – Ca regulates contraction
of all muscles, blood clotting, transmission of nerve impulses
-hypercalcemia causes depression of CNS, hypocalcemia causes overexcitement of CNS
-most Ca is stored in bones (98.9%) which release Ca when extracellular fluid Ca decreases
-85% of phosphate in body is stored in the bones, 15% in cells and 1% in extracellular fluid
Ca in Plasma and Interstitial Fluid – 41% of Ca in plasma is combined with proteins and
nondiffusible, 9% is diffusible but bound to anionic substances like phosphate, and 50% is
diffusible AND ionized and can cross capillary membrane
-normal plasma Ca ion concentration of about 1.2mm/L, controlling many effects in the body
Inorganic Phosphate in Extracellular Fluids – comes in 2 forms: HPO4 and H2PO4
-HPO4 is normally 1.05mm/L and H2PO4 is 0.26mm/L; when total amount rises, both rise
-when pH becomes acidic, there is relative increase of H2PO4 and decrease in HPO4, and
opposite occurs when extracellular fluid becomes alkaline
-often expressed as phosphorus per deciliter
Nonbone Physiologic Effects of Altered Ca and PO4 in body fluids – increases in concentrations
does not cause major immediate effects, but decreases in extracellular fluid causes BIG changes
Hypocalcemia Causes Nervous System Excitement and Tetany – when extracellular fluid falls
below normal, CNS becomes more excitable because it causes increased membrane
permeability to Na ions allowing easy action potentials
-at concentrations of <50%, neurons are so excitable that they begin to discharge spontaneously
to elicit peripheral muscle tetany and can cause seizures
-tetany occurs when blood concentration reaches 9.4mg/dl
Hypercalcemia Depresses CNS and Muscle Activity – above normal levels, CNS becomes
depressed and reflexes are sluggish, and QT interval of heart decreases and causes lack of
appetite and constipation; above 17mg/dl causes CaPO4 crystals to form
Absorption and Excretion of Ca and PO4
1. Intestinal Absorption and Fecal Excretion of Ca and PO4 – usual intakes are
1000mg/day, and normally Ca ions are poorly absorbed without help of Vitamin D (35%
of Ca absorbed while the remaining is excreted). Additional 250mg/day enters
intestines by GI juices and sloughed cells so a total of 90% of all Ca is excreted in the
feces.
a. Absorption of PO4 is easy, and excretion occurs in combination with Ca
2. Renal Excretion of Ca and PO4 – 10% of ingested Ca excreted in urine. 41% of plasma
Ca bound to plasma proteins and not filtered by glomerular capillaries. Rest is
combined with anions like PO4 or ionized (50%) and filtered in glomeruli
a. Renal tubules reabsorb 99% of filtered Ca and 100mg/day excreted in urine
b. 90% of Ca is reabsorbed in proximal tubules, loops of henle, distal tubules
c. In late tubules, reabsorption depends on levels in the blood
d. When Ca is low, reabsorption is great and almost no Ca is lost in urine
e. Minute increase in blood Ca increases Ca excretion a lot, controlled by PTH
f. Renal phosphate excretion is controlled by an overflow mechanism; when PO4
is below critical value of 1mm/L, all PO4 in glomerular filtrate is reabsorbed and
no phosphate is lost
i. Above this value, rate of PO4 loss is directly proportional to additional
increase
ii. Kidneys regulate phosphate concentration in extracellular fluid by
altering rate of phosphate excretion in accordance with plasma
concentration
iii. PTH can greatly increase phosphate excretion by kidneys
Bone and its relation to extracellular Ca and PO4 – bone is tough organic matrix enhanced by
Ca
-compact bone is 30% matrix and 70% salts
Organic Matric of Bone – 95% collagen fibers and gelatinous ground substance to give tensile
strength; ground substance composed of extracellular fluid + proteoglycans of chondroitin
sulfate and hyaluronic acid
Bone Salts – crystalline salts deposited in organic matrix are Ca and PO4; combination is called
hydroxyapatite Ca10(PO4)6(OH)2
-Mg, Na, K, and CO3 are also present in bone salts, conjugated to crystals
-radioactive substances can conjugate and stay, can cause osteosarcoma
Tensile and Compressional Strength of Bone – arrangement of collagen and hydroxyapatite
bonding prevents “shear” in bone; prevents slipping out of place to provide strength in bone
and Ca provides great compression strength
Precipitation and Absorption of Ca and PO4 in Bone – Equilibrium with Extracellular Fluids
1. Hydroxyapatite does not precipitate in EC fluid despite supersaturation of Ca and PO4 –
inhibitors are present in body to stop hydroxyapatite from precipitating, such as pyrophosphate
2. Mechanism of Bone Calcification – initial stage is secretion of collagen molecules and ground
substance by osteoblasts, which polymerize to form fibers to become an osteoid, similar to
cartilage but Ca deposits can precipitate
-as osteoid is formed, osteoblasts are entrapped and become quiescent, becoming osteocytes
-Ca begins to precipitate on collagen fibers that multiple to become hydroxyapatite precursors
-over time, amorphous salts converted to hydroxyapatite crystals over weeks or months
-amorphous salts can be absorbed when body needs calcium
Precipitation of Ca in Nonosseous Tissues under Abnormal Conditions – Ca never precipitates
in tissues besides bone unless under abnormal conditions, such as atherosclerosis
Ca exchange between bone and extracellular fluid – importance of exchangeable Ca in bone is
that it provides rapid buffering mechanism to keep extracellular Ca concentration in
extracellular fluids from rising to excessive levels
Deposition and Absorption of Bone – bone is deposited by osteoblasts and absorbed by
osteoclasts (osteoblasts found on outer surfaces of bones)
-osteoclasts are monocyte derived, bone absorbing cells controlled by PTH
-osteoclasts send out villus-like projectionstoward bone and secrete proteolytic enzymes and
acids (citric acid and lactic acid)
-enzymes digest/dissolve matrix and acid dissolves bone salts
-PTH binds to receptors on adjacent osteoblasts causing them to release osteoprotegerin ligand
(OPGL), also called RANK ligand, which activates receptors on osteoclast precursor
-Osteoblasts also secrete osteoprotegerin (OPG) also called osteoclastogenesis inhibitory
factor (OCIF), a cytokine which inhibits bone resorption
-OPG opposes bone resorption activity of PTH
-Vitamin D and PTH stimulate osteoclast through inhibiting OPG production and
stimulating OPGL formation; estrogen stimulates OPG production
-bone deposition and resorption are in equilibrium so total mass becomes constant
-bone is deposited in circles (lamellae) until tunnel is filled; leaving haversian canal
-bone adjusts in strength depending on degree of bone stress (thicken with heavy loads)
-shape of bone can adjust, and because old bones are weak and brittle, remodeling is important
-repair of fracture activates osteoblasts
Vitamin D – potent effect increases Ca absorption from intestine and effects
deposition/resorption; vitamin D converted to active form 1,25-dihydroxycholecalciferol
1. cholecalciferol (vitamin D3) if formed in the skin – vitamin D3 is formed in skin as a
result of irradiation of 7-dehydrocholesterol by UV
2. cholecalciferol converted to 25-hydroxycholecalciferol in liver – has a feedback
inhibitory step on conversion, important because it regulates concentration of 25hydroxycholecalciferol in plasma to promote excessive action of vitamin D, and also,
controlled conversion of vitamin D conserves it in liver for future use
3. Formation of 1,25-dihydroxycholecalciferol in kidneys and control by PTH – occurs in
proximal tubules to form the most active form of vitamin D, it requires PTH
4. Ca Ion concentration controls formation of 1,25-dihydroxycholecalciferol – plasma
concentration of 1,25(OH)D3 is inversely affected by plasma Ca, because Ca ion itself
has influence on preventing conversion of 25 hydroxycholecalciferol  1,25(OH)D3, and
even more important, PTH is greatly suppressed when Ca concentration is high
a. When PTH is high, 25-hydroxycholecalciferol  24,25-dihydroxycholecalciferol
which has no Vitamin D effect
-active vitamin D increases absorption of Ca and PO4 in extracellular fluid and contributes to
negative feedback
-vitamin D receptors are on most cells in nuclei, and has hormone/DNA binding domains
-vitamin D receptor forms complex with retinoid-X receptor, which binds DNA and activates
transcription
-in some cases, vitamin D inhibits transcription; vitamin D receptor has 1000x more
affinity for 1,25(OH)D3 than 25-hydroxycholecalciferol
Hormonal effect of Vitamin D to promote instestinal Ca absorption – 1,25(OH)D3 is a hormone
that promotes intestinal absorption of Ca by forming calbindin, a Ca binding protein on
epithelial receptors on brush borders that functions in transport into cell cytoplasm
-rate of Ca absorption directly proportional to quantity of CALBINDIN
-also upregulates calcium-stimulated ATPase and Alkaline phosphatase in epithelial cells
Vitamin D promotes phosphate absorption by intestines – normally PO4 easily absorbed, but it
is enhanced with vitamin D from direct effect of 1,25(OH)D3
Vitamin D decreases renal Ca and PO4 excretion – decreases substances in urine
Effect of Vitamin D on Bone and PTH – administration of vitamin D causes absorption of bone,
and in absence of vitamin D, PTH associated bone absorption is reduced/prevented
-in small quantities, vitamin D promotes bone calcification
Parathyroid Hormone – regulates intestinal absorption, renal excretion, and exchange between
extracellular gluid and bone of these ions
Anatomy of Parathyroid Glands – 4 parathyroid glands behind thyroid gland
-removal of 1 or 2 of these causes no major anomalies, but removal or 3-4 causes
hypoparathyroidism, and a small portion of the gland can hypertrophy to take over function
-parathyroid gland contains chief cells (PTH secretion) and oxyphil cells (not known function)
Effect of Parathyroid Hormone on Ca and PO4 concentrations – causes Ca concentration to rise
and PO4 concentration to fall faster
-PTH increases Ca and PO4 absorption from bone and decrease excretion of Ca by kidneys
PTH increases Ca and PO4 absorption from bone – two effects on bone to cause absorption:
1. Rapid phase (osteolysis) begins in minutes and increases for several hours and results
from activation of already existing bone cells to promote Ca and PO4 absorption
a. Occurs in the bone matrix in vicinity of osteocytes in bone, and also in vicinity of
osteoblasts along bone surface
b. Osteocytic Membrane system composed of osteoblasts and osteocytes
separates bone from extracellular fluid
c. Bone fluid – between osteocyte membrane and bone, where Ca is pumped
from bone into this fluid creating Ca concentration in bone 1/3 of EC fluid.
Activation of osteocytic pump reduces concentration in bone even more, called
osteolysis
d. Cells express receptors for PTH, which can activate Ca pump and cause rapid
removal of CaPO4 salts from amorphous bone
i. Stimulates pump by increasing Ca permeability of bone fluid side of
osteocytic membrane, allowing Ca to diffuse into membrane cells from
bone fluid
2. Slower phase taking weeks and results from proliferation of osteoclasts and followed by
osteoclastic resorption of the bone itself
a. PTH has better known effect by activating osteoclasts, but osteoclasts do not
have receptor for PTH; believed that osteoblasts send secondary signal TO
osteoclasts called osteoprotegerin ligand which activates receptors on
preosteoclastcells and transforms them into mature osteoclasts
b. Occurs in 2 steps: immediate activation of osteoclasts and formation of new
osteoclasts (takes several days of excess PTH for osteoclastic system to become
well developed)
c. A few months of excess PTH can cause weakened bones and secondary
stimulation of osteoblasts to correct weakened state
Parathyroid hormone deceases Ca excretion and increases PO4 excretion by kidneys – also
increases rate of reabsorption of Na, K+, and amino acids
-inceased Ca absorption occurs in late distal tubules, collecting tubules and early collecting ducts
-without PTH, continual loss of Ca would deplete both extracellular fluid and bone Ca
Parathyroid Hormone increases intestinal absorption of Ca and PO4 – does this by increasing
formation of 1,25-OH2D3 from Vit D
-cAMP mediates effects of PTH – after few minutes of PTH administration, cAMP increases in
osteocytes, osteoclasts, and other cells, which is responsible for osteoclastic secretion of
enzymes and acids to cause bone reabsorption and formation of 1,25-OH2D3
Control of Parathyroid Secretion by Ca Ions – slightest decrease in Ca concentration in EC fluid
causes parathyroid glands to increase rate of secretion, and cause hypertrophy if persists
-parathyroids become enlarged in rickets and pregnancy, greatly enlarged in lactation
-parathyroids decrease in size with increases in Ca concentration such as excessive Ca in diet,
increased vitamin D in diet, bone absorption other than PTH
-changes in EC fluid are detected by calcium-sensing receptor (CaSR) in parathyroid cell
membranes (G-protein stimulated by Ca2+ activates inositol triphosphate and diacylglycerol
which  increases Ca from intracellular stores to  DECREASE PTH
-decreased EC fluid Ca inhibits these pathways and stimulates PTH secretion
Summary – PTH stimulates bone resorption causing release of Ca into EC fluid, PTH increases
reabsorption of Ca and decreases PO4 reabsorption from kidneys, leading to decreased
excretion of Ca and increased excretion of PO4, and PTH is necessary for activating Vitamin D
Calcitonin – peptide hormone secreted by the thyroid gland DECREASES plasma Ca and has
opposite effects to PTH
-synthesis of calcitonin occurs in parafollicular cells or C cells in interstitial fluid between
follicles of thyroid gland, and are remnants of ultimobranchial glands of lower animals
Increased plasma Ca stimulates Calcitonin secretion – contrasts to PTH secretion, stimulated by
decreased calcium concentration
Calcitonin DECREASES plasma calcium in two ways:
1. decreases absorptive activities of osteoclasts and osteolytic effect of osteocytic
membrane throughout bone, shifting balance in favor of Ca deposition
2. decreased formation of new osteoclasts; because osteoclastic resorption of bone leads
to osteoblastic activity, decreased of osteoclasts followed by decreased numbers of
osteoblasts, and long term effect is LITTLE on Ca concentration
-Calcitonin has WEAK effect on plasma concentration in adult human – reasons for weak effect
is 3-fold
1. any initial reduction in Ca ions caused by calcitonin leads to powerful PTH effect
2. When thyroid gland is removed and no more calcitonin is present, little effect on long
term blood concentration is noted
3. Daily rates of absorption and deposition of Ca are small, even after rate of absorption
is slowed by calcitonin
4. Calcitonin is more prominent in children, when bone remodeling is greatest
-Paget Disease – osteoclastic activity is greatly increased, calcitonin has much more powerful
effect on reducing calcium absorption
Buffer Function of Exchangeable Calcium in Bones – First line of Defense – exchangeable Ca in
bones are the amorphous calcium compounds which cause immediate exchange upon increases
or decreases of concentration
Hormonal Control of Ca Ion Concentration – Second Line of Defense – at the same time that
exchangeable calcium is buffering, both parathyroid and calcitonin hormonal effects are at play
-within few minutes of increase in Ca ion concentration, rate of PTH secretion decreases,
calcitonin increases
-only PTH mechanism seems to be important in maintaining normal plasma Ca
Pathophysiology of PTH, Vitamin D, and Bone Disease
1. Hypoparathyroidism – with insufficient PTH, osteocytic resorption and exchangeable Ca
decreases and osteoclasts become inactive
-calcium reabsorption from bones is depressed that level of Ca in body fluids decreases,
bone usually remains strong
-when parathyroids are removed, Ca in blood falls and can cause tetany of laryngeals
-treatment of hypoparathyroidism is usually with PTH and Vitamin D
2. Primary Hyperparathyroidism – abnormality of parathyroids causes excess PTH secretion
usually do it a tumor; causes extreme osteoclastic activity in the bones and elevates Ca in the EC
fluid while depressing concentration of phosphate because of increased renal excretion
-Bone disease in Hyperparathyroidism – severe disease cause osteoclast absorption to exceed
osteoblast deposition, and bone may be eaten away entirely. Cystic bone disease of
hyperparathyroidism is called osteitis fibrosa cystica
-osteoblastic activity increases greatly to try to make up for this, and secrete alkaline
phosphatase, causing high levels of AlkPhos in the blood
-Effects of hypercalcemia in Hyperparathyroidism – depression of CNS, muscle weakness, ab
pain, peptic ulcer, lack of appetite, and depressed relaxation of heart
-Parathyroid poisoning and Metastatic Calcification – when extreme PTH levels secreted, level
of Ca in body fluids rises rapidly, causing supersaturation of Ca and PO4 in the blood, so CaPO4
crystals begin to deposit in alveoli of lungs, kidney tubules, thyroid, stomach
-Formation of Kidney Stones in hyperparathyroidism – excess Ca and PO4 absorbed by
intestines must be excreted by kidneys, causing proportionate increase in urine, causing
precipitation in kidney to form kidney stones
-CaOxalate stones can develop as well
Secondary Hyperparathyroidism – high levels of PTH occur as compensation for hypocalcemia
and not as a result of overactive parathyroids secreting PTH
-can be caused by vitamin D deficiency or chronic renal disease which causes insufficient active
vitamin D production
-vitamin D deficiency leads to osteomalacia and high levels of PTH cause absorption of bones
Rickets caused by Vitamin D deficiency – in children, Ca or PO4 deficiency in EC fluid causes
rickets due to lack of vitamin D
-exposure to sun converts 7-dehydrocholesterol to vitamin D3 to preven rickets
-Plasma Ca and PO4 decreases in rickets – plasma Ca in rickets is only slightly depressed, but
PO4 is greatly depressed because parathyroids prevent Ca level from falling by promoting bone
absorption every time Ca levels fall
-no good regulatory mechanism for preventing a falling level of phosphate
-Rickets weakens the bones – marked compensatory increase in PTH secretion causes extreme
osteoclastic absorption of bone to cause bone to become progressively weaker and imposes
marked stress on bone and causing extreme osteoblastic activity as well, which builds osteoid
without calcium, causing uncalcified, weak osteoid to replace older bone being reabsorbed
-tetany in rickets – doesn’t occur in early stages of rickets because parathyroids continually
stimulate osteoclastic absorption of bone, but when bones become exhausted of Ca, level of
calcium falls rapidly, to cause tetany
-treatment of rickets – treatment of rickets depends on supplying adequate Ca and PO4 in diet
and also large amounts of vitamin D
-Osteomalacia (adult rickets) – serious deficiencies of vit d and Ca occur as a result of
steatorrhea (failure to absorb fat) because vitamin D is fat-soluble and Ca tends to form
insoluble soaps with fat, both passing into feces. Doesn’t cause tetany, but causes severe bone
disability
-Osteomalacia and Rickets Caused by Renal Disease – prolonged kidney damage causes failure
of kidney to form 1,25(OH)D3, and if it is damaged, renal rickets is severe
-congenital hypophosphatemia – results from congenitally reduced reabsorption of
phosphates by renal tubules and must be treated with phosphate compounds instead of
Ca and vitamin D, also called vitamin D-resistant rickets
-Osteoporosis – most common of all bone diseases and results from diminished organic bone
matrix rather than poor bone calcification
-osteoblastic activity is low, and rate of bone osteoid deposition is less
-main causes are: lack of physical stress on bones, malnutrition, lack of vitamin C (necessary for
secretion of intercellular substances by all cells such as osteoid), postmenopausal lack of
estrogen secretion because estrogens decrease number and activity of osteoclasts, old age,
where growth hormone and factors diminish, and cushing’s syndrome – because massive
glucocorticoids are secreted in this disease to cause decreased deposition of protein throughout
the body and increased catabolism of protein and have specific effect of depressing osteoblastic
activity
Physiology of Teeth – teeth grind, cut, and mix food; upper sets of teeth fit with lower set,
called occlusion
Enamel – outer layer of enamel created by ameloblasts; once erupted and covers surface of
tooth, no more enamel is made. Enamel is hard, much harder than dentin, makes it resistant to
acids, enzymes, and other corrosive agents
Dentin – main body of tooth composed of dentin, which is strong and bony; made up of
hydroxyapatite crystals similar to bone but much denser inside collagen fibers
-made by odontoblasts
-calcium salts in dentin make it resistant to compressional forces
Cementum – bony substance secreted by peridontal membrane lining tooth socket. Cementum
holds teeth in place, and when teeth are exposed to excessive strain, cementum becomes
thicker and stronger
Pulp – pulp cavity is filled with pulp, composed of connective tissue with an abundant supply of
nerve fibers, blood vessels, and lymphatics
-lined by odontoblasts which secrete dentin, but also encroach onto pulp as we age
-dentinal tubules are projected into dentin and involved in exchange of Ca, PO4, and
other minerals
Dentition – humans develop 2 sets of teeth; first is called deciduous teeth, and have 20 in
number; permanent teeth occur later
Formation of Teeth – invagination of oral epithelium into dental lamina followed by
development of tooth-producing organ; epithelial cells above form ameloblasts, and below form
odontoblasts
Eruption of Teeth – growth of bone shoves tooth upward
Development of permanent teeth – a tooth-forming organ develops in deeper dental lamina for
each permanent tooth that will be needed after deciduous teeth are gone and slowly form for
the first 6-20 years of life
-permanent tooth pushes forward and erodes the root of deciduous tooth to cause it to loosen
and fall out
Metabolic Factors Influence Development of Teeth – accelerated by thyroid and growth
hormones, and deposition of salts in early forming teeth affected by Ca and PO4 in diet and
vitamin D present, and rate of PTH secretion
Mineral exchange in teeth – salts of teeth are composed of hydroxyapatite with associated ions,
and are constantly being deposited while old salts are being reabsorbed from teeth
-deposition and reabsorption occur mainly in dentin and cementum to limited extent, occur
mainly through exchange of minerals with saliva by diffusion
-rate of absorption and deposition of minerals in cementum is equal to that of surrounding bone
of jaw, where is deposition and absorption of minerals in dentin is 1/3 that of bone
-continual mineral exchange happens in dentin and cementum
Dental Abnormalities – most common are caries (erosion of teeth) and malocclusion (failure of
projections of upper and lower teeth to interdigitate properly)
Caries and the rold of bacteria and ingested carbs – most common bacteria in caries of tooth is
streptococcus mutans; first event is deposit of a plaque (film of precipitated products of saliva
and food on teeth)
-large numbers of bacteria inhibit plaque and available to cause caries
-these bacteria depend on carbs for their food
-they form acids and proteolytic enzymes, which cause caries because calcium salts of teeth are
slowly dissolved in high acidic medium; once salts have been absorbed, the matrix is rapidly
digested by enzymes
-enamel of teeth is primary barrier to development of caries; once carious process has passed
enamel, to dentin, process proceeds rapidly
-high carb diet causes more frequent caries
Role of Fluorine in Preventing Caries – fluorine does not make enamel harder, but does replace
OH ions in hydroxyapatite when makes enamel less soluble, and fluorine may be toxic to
bacteria
-fluorine is believed to promote deposition of CaPO4 to heal enamel surface when pits develop
from caries
Malocclusion – caused by hereditary abnormality that causes teeth of one jaw to grow to
abnormal positions, and teeth do not interdigitate properly and cannot perform normal grinding
action
-results in abnormal placement of lower jaw in relation to upper jaw and cause undesirable
effects such as pain in mandibular joint and deterioration of teeth