Regulation of Calcium and Phosphate Metabolism (Dr. Lopez) Flashcards
Calcium Homeostasis
- Almost every Cell in our Body uses Calcium in some way
a) The Extracellular Calcium Concentration has a Dramatic Effect on the Excitability of Cells (Particularly Nerve Fibers) - Calcium is Stored in Bones
- Calcium Homeostasis is Tightly Regulated
- During Aging, there are DECREASES in the amount of Calcium absorbed from Dietary Intake, and in Dietary Intake of Calcium
a) Existing Bone Cells are Reabsorbed by the Body FASTER than NEW BONE is MADE
b) Aging Contributes to Osteopenia or Osteoporosis
Distribution of Calcium in the Body
Percent Distribution of Total Calcium
1) ECF: 0.1%
2) Plasma: 0.5%
3) ICF: 1%
4) Bones and Teeth/ rest : 99%
- Free ionized Ca2+ is the BIOLOGICALLY ACTIVE Form
- Of that total, only 50% of the unbound Ca2+ is Ionized!
Changes in the Plasma Ca2+ are Physiologically Significant
1) HYPOCALCEMIA: Decrease in Plasma Ca2+ Concentration
a) SYMPTOMS:
- Hyperreflexia, Spontaneous Twitching, Muscle Cramp, Ringling, and Numbness
b) INDICATIONS:
- CHOVSTEK SIGN: Twitching of the FACIAL MUSCLE elicited by Tapping on the FACIAL Nerve
- TROUSSEAU SIGN: Carpopedal Spasm upon inflation of a Blood Pressure Cuff
2) HYPERCALCEMIA: Increase in Plasma Ca2_ Concentration
a) SYMPTOMS:
- Decreased QT Interval, Constipation, Lack of Apetite, Polyuria, Polydipsia, Muscle Weakness, Hyporeflexia, Lethargy, Coma
Plasma Ca2+ Concentration Influences Membrane Excitability!
Extracellular Calcium = PLASMA Calcium
1) LOW EXTRACELLULAR Ca2+: HYPOCALCEMIA
- Reduces the activation Threshold for Na+ Channels —-> Easier to Evoke AP (Less or no Stimulus required to Trigger AP)
- Results in INCREASE in Membrane Excitability (Spontaneous APs)
- Generation of Spontaneous AP is the Physical Basis for HYPOCALCEMIA TETANY (Spontaneous Muscle Contractions due to LOW Extracellular Ca2+)
- Produces Tingling and Numbness (On Sensory Neurons) and Spontaneous Muscle Twitches (On Motoneurons and Muscle)
2) HIGH EXTRACELLULAR Ca2+: HYPERCALCEMIA
- Opposite of Hypocalcemia Mechanism (Decrease Membrane Excitability)
- Nervous System becomes DEPRESSED and REFLEX Responses are SLOWED
Changes in Calcium Concentration
The Forms of Ca2+ in the Plasma Can be altered by:
1) Changes in Plasma Protein Concentration
- Alter Total Ca2+ Concentration in the Same Direction (Ex: INCREASE Plasma Protein Concentration, INCREASE Total Ca2+ Concentration)
- NO Change in Ca2+ IONIZED
2) Changes in Anion Concentration
- Change the Fraction of Complexed with Anions
- Ex if INCREASE Phosphate Concentration, DECREASED Ionized Ca2+ Concentration
3) Acid/ Base Abnormalities
- Alter the ionized Concentration by Changing the Fraction of Bound to Albumin
Acid-Base Abnormalities alter Ionized Ca2+ Concentration
ACIDEMIA:
- Free Ionized Ca2+ Concentration INCREASES because Less Ca2+ is bound to Albumin
ALKALEMIA:
- Free Ionized Ca2+ Concentration DECREASES, often accompanied by HYPOCALCEMIA
Calcium Homeostasis is tightly regulated
Involves the Coordination Action of:
- 3 Organ Systems: Bone, Kidney, and Intestine
- 3 Hormones: PTH, Calcitonin, and Vitamin D
Calcium Homeostasis
BONE Remodeling:
- NO net GAIN or LOSS of Ca2+
- New Bone is formed (Deposited)
- Old Bone is Resorbed
**To maintain Ca2+ Balance, Kidneys must excrete the same amount of Ca2+ that is absorbed by the GI Tract!!!
Relationships between Ca2+ and Phospahte
PHOSPHATE:
- Critical for Biological Processes:
a) Component of ATP, Second Messenger Molecules, DNA, RNA, and Phospholipids
b) Intracellular Anion
c) Involved in Activation and Deactivation of Enzymes
d) Buffer in Bone, Serum, and Urine
PERCENT Distribution of Pi:
a) Bone: 85%
b) Plasma : 1%
- 84% Ionized
- 10% Protein Bound
- 6% Complexed (to various Cations, including K+ and Na+)
c) ICF: 15%
Relationship between Ca2+ and Phosphate
PHOSPHATE:
- Extracellular Concentration of Pi is INVERSELY related to that of Ca2+
a) EXTRACELLULAR CONCENTRATION of Pi is REGULATED BY THE SAME HORMONE THAT REGULATES Ca2+ CONCENTRATION
b) Normal Range of Extracellular is 2.5 to 4.5 mg/dL
PTH is Synthesized in and Secreted from the Parathyroid Glands
1) Four Parathyroid Glands
- 2 Superior
- 2 Inferior
2) Sit POSTERIOR on the Thyroid
3) The CHIEF Cells of the Parathyroid glands Synthesize and Secrete PTH
PTH Regulates the Concentration of Ca2+ and Pi in Plasma
- PEPTIDE HORMONE
- Single Chain Polypeptide with 84 aa
- Synthesized on Ribosomes as preproPTH (115 aa), then its is cleaved to form proPTH (90aa), followed by Transportion to Golgi and further cleavage to form PTH
- Packaged in SECRETORY GRANULES
- **PTH REGULATES THE CONCENTRATION OF Ca2+ in PLASMA:
a) Stimuli for Secretion: DECREASE Plasma Ca2+
b) INCREASE in Extracellular Ca2+ Concentration INHIBITS PTH Synthesis and Secretion
Regulation of PTH Gene Expression and Secretion
1) Chronic HYPERCALCEMIA:
- Long term INCREASE Ca2+ Plasma Concentration
- Causes DECREASED Synthesis and Storage of PTH, INCREASED breakdown of Stored PTH and release of Inactive PTH Fragment into the Circulation
2) Chronic HYPOCALCEMIA
- Long Term DECREASED Ca2+ Plasma Concentration
- Causes INCREASED Synthesis and Storage of PTH and Hyperplasia of Parathyroid Glands (SECONDARY HYPERPARATHYROIDISM)
3) MAGNESIUM
- Parallel but LESS SIGNIFICANT Effects on PTH Secretions
- **An Exception: SEVERE HYPOMAGNESEMIA
- Results in Chronic Mg2+ Depletion, as in ALCOHOLISM)
- Inhibition of PTH Synthesis, Storage, and Secretion
- **NOTE:
- PTH acts via G PROTEIN LINKED RECEPTOR!!!!!!!!!!!
Actions of PTH on Bone, Kidney and Intestines
-*** Decreases Plasma [Ca2+] INCREASES PTH Secretion
1) BONE:
- Bone Resorption
2) KIDNEY:
- Decrease Pi Absorption (Phosphaturia)
- INCREASES Ca2+ Reabsorption
- INCREASES Urinary cAMP
3) INTESTINE:
- INCREASES Ca2+ Absorption (Via Vitamin D)
Vitamin D promotes Mineralization of New Bone through its coordinated actions in the Regulation of both Ca2+ and Pi plasma Concentration
- INCREASE both Ca2+ and Pi Plasma Concentrations
- INCREASE Ca2+ x Pi Product to promote Mineralization of New Bone
- Like PTH, has actions in Intestine, Kidney, and Bone
Vitamin D = CHOLECALCIFEROL
- a PROHORMONE
- Itself is Physiologically INACTIVE
- Must be Successively HYDROXYLATED to an Active Metabolite (Regulated by Negative Feedback Mechanism)
Two Sources:
- Ingested in Diet
- Synthesized in Skin from 7- Dehydrocholesterol in there presence of UV Light
Vitamin D is a STEROID HORMONE!!!!
Regulation of Vitamin D Synthesis
1) 7 Dehydrocholesterol
- UV Light on Skin
2) Cholecalciferol
- From Diet
(Converted to next step by 25-Hydroxylase in LIVER)
3) 25-OH Cholecalciferol
a) 1 ALPHA HYDROLYXASE (In Renal Tubule)
b) 24- Hydroxylase
4a) 1,25 OH- Cholecalciferol (ACTIVE)
4b) 24,25 (OH)2- Cholecalciferol
(INACTIVE)
*Kidney 1-ALPHA Hydroxylase Enzyme is tightly regulated at the Transcriptional Level!!!
Physiology of Bone
1) PTH:
- PTH Receptors located on OSTEOBLASTS NOT Osteoclasts
- SHORT TERM ACTIONS: BONE FORMATION (Via DIRECT Action on Osteoblast)
- *** Basis for the use of Intermittent Synthetic PTH Administration in Osteoporosis Treatment
- LONG TERM ACTIONS: INCREASE BONE RESORPTION (INDIRECT Action on Osteoclasts mediated by Cytokines released from Osteoblasts)
2) Vitamin D:
- Acts Synergistically with PTH to Stimulate OSTEOCLAST Activity and Bone Resorption
Summary of Agents/ Factors involved in Bone Formation and Resorption
1) M-CSF (Macrophage Colony- Stimulating Factor):
- Induces Stem Cells to differentiate into Osteoclast precursors, Mononuclear Osteoclasts, and finally, Mature MULTINUCLEATED Osteoclasts
2) RANKL (Receptor Activator for NF-kB Ligand)
- Cell Surface Protein produced by Osteoblasts, Bone Lining Cells, and Apoptotic Osteocytes
- PRIMARY MEDIATOR of OSTEOCLAST FORMATION
3) RANK:
- Cell surface Protein Receptor on Osteoclasts and Osteoclast Precursors
4) OPG (Osteoprotegerin):
- Soluble Protein produced by Osteoblasts
- Decoy Receptor for RANKL
- INHIBITS RANKL/ RANK Interaction
5) Osteoclast Formation
- RANKL/OPG
Specific Actions of PTH and Vitamin D on Bone Formation and Resorption
1) PTH:
- INCREASES RANKL
- DECREASES OPG
2) VITAMIN D:
- INCREASES RANKL
Mechanisms of Action of PTH on Kidney
LUMEN Side:
- Inhibition of NTP by PTH causes PHOSPHATURIA!!!
- INCREASES Excretion of Pi in Urine
INSIDE CELL:
- The cAMP generated in Cells of the Proximal Tubule is EXCRETED in Urine: URINARY cAMP
***The Second Renal Action of PTH is on the DISTAL CONVOLUTED TUBULE and Complements the INCREASE in Plasma [Ca2+] that resulted from the Combination of Bone Resorption and Phosphaturia
Actions of Vitamin D on Kidney
- Stimulates both Ca2+ and Pi Reabsorbtion
Summary of PTH Actions on Ca2+ and Pi Homeostasis
1) SMALL INTESTINE
- NO DIRECT Action
2) BONE
- Promotes Osteoblastic Growth and Survival
- Regulates M-CSF, RANKL, and OPG Production by Osteoblast
- Chronic INCREASE Levels promote NET Ca2+ and Pi from Bone
3) KIDNEY
- Stimulates 1ALPHA HYDROXYLASE Activity
- Stimulates Ca2+ Reabsorption by the THICK ASCENDING LIMB of HENLE’S LOOP and the DISTAL TBULE
- INHIBITS Pi REABSORPTION by Proximal Nephrons (Repressed NPT2a Expression)
4) PARATHYROID GLAND
- NO DIRECT Actions
Summary of Vitamin D Actions on Ca2+ and Pi Homeostasis Cont
1) SMALL INTESTINE
- INCREASES Ca2+ and Pi Absorption by INCREASING CALBINDIN Expression
2) BONE
- Sensitizes OSTEOBLASTS to PTH
- Regulates Osteoid Production and Calcification
3) KIDNEY
- Promotes Pi Reabsorption by Proximal Nephrons (Stimulates NPT2a Expression)
- Minimal Actions of Ca2+
4) PARATHYROID GLAND
- DIRECLY INHIBITS PTH Gene Expression
- DIRECTLY STIMULATES CaSR Gene Expression
Calcitonin Actions
- Primary Actions on BONE and KIDNEY
- DECREASES Blood Ca2+ and Pi Concentration by INHIBITING Bone Resorption (Effects occur ONLY at High Circulation levels of the Hormone)
a) DECREASES activity and DECREASES number of Osteoclasts
b) Calcitonin Receptors expressed on OSTEOCLASTS
c) Major Stimulus: INCREASE Plasma [Ca2+]
- No Role in Chronic (Minute to Minute) Regulation of Plasma [Ca2+]
a) THYROIDECTOMY: Decreases Calcitonin but NO Effect on Ca2+ Metabolism
b) THYROID TUMORS: Increases Calcitonin but NO Effect in Ca2+ Metabolism
Primary Hyperparathyroidism
- Patients EXCRETE EXCESSIVE amounts of Pi, cAMP, and Ca2+
( Ca2+- Oxalate Stones) - ** “Stones”, “Bones”, and “Groans” *******
a) Hypercalciuria: Stones
b) Increased Bone Resoprtoin: Bones
c) Constipation: Groans
Treatment usually requires PARATHYROIDECTOMY!!!*
Primary Hyperparathyroidism Hormone Levels
1) PTH
- INCREASES
2) Ca2+
- INCREASES
3) Pi
- DECREASES
4) Vitamin D
- INCREASES
Secondary Hyperparathyroidism
- INCREASE in PTH Levels is SECONDARY to LOW [Ca2+] in Blood
- Causes for the LOW [Ca2+] in Blood include:
a) Renal Failure
b) Vitamin D Deficiency
Secondary Hyperparathyroidism Hormone Hormone Levels
1) RENAL FAILURE
a) PTH:
- Increases
b) Ca2+
- Decreases
c) Pi
- Increases
d) Vitamin D
- Decreases
2) VITAMIN D DEFICIENCY
a) PTH:
- Increases
b) Ca2+
- Decreases
c) Pi
- Decreases
d) Vitamin D
- Decreases
3) HYPOCALCEMIA:
a) PTH:
- Increases
b) Ca2+
- Decreases
c) Pi
- Decreases
d) Vitamin D
- Increases
4) HYPERPHOSPHATEMIA
a) PTH:
- Increases
b) Ca2+
- Increases
c) Pi
- Increases
d) Vitamin D
- Decreases
Hypoparathyroidism
CAUSES:
1) Thyroid Surgery
2) Parathyroid Surgery
3) Autoimmune or Congenital (Less Common)
MOST SYMPTOMS ARE ASSOCIATED with DECREASED Ca2+:
1) Muscle Spasms or Cramping
2) Numbness, Tingling, or Burning, especially around the Mouth and Fingers
3) Seizures
4) In Kids, Poor Teeth development, Mental Deficiency
TREATMENT:
- Oral Ca2+ Supplement and Active form of Vitamin D
Hypothyroidism Hormone Levels
PTH:
- Decreased
Ca2+
- Decreased
Pi
- Increased
Vitamin D
- Decreased
ALBRIGHT Hereditary Osteodystrophy (Pseudohypoparathroidism Type 1a)
- INHERITED AUTOSOMAL DOMINANT Disorder, Gs for PTH in Bone and Kidney is DEFECTIVE!!!
- HYPOCALCEMIA and Hyperphosphatemia Develop
- INCREASED PTH Levels
- ** Administration of Exogenous PTH Produces NO Phosphaturic Response and NO Increase Urinary cAMP
ALBRIGHT Hereditary Osteodystrophy (Pseudohypoparathroidism Type 1a) Hormone Levels and Phenotype
PTH
- Increased
Ca2+
- Decreased
Pi
- Increased
Vitamin D
- Decreased
PHENOTYPE:
- Short Stature
- Short Neck
- Obesity
- Subcutaneous Calcification
- Shortened Metatarsals and Metacarpals
Humoral Hypercalcemia of Malignancy
- HYPERCALCEMIC Syndrome associated with malignancy
- PTH Related Peptide (PTHrP) is a peptide produced by Tumors with Close Homology in the N-Terminal to PTH (Product of Gene Duplication of PTH)
- **Binds and ACTIVATES Same Receptor as PTH (Type 1 PTH Receptor)
Humoral Hypercalcemia of Malignancy
- INCREASED PTHrP Levels
- Produced Similar Profiles to Primary Hyperparathyroidism
a) Increased Urianry Ca2+, Increased Urinary Pi, Increased cAMP
b) Increased Blood Ca2+ (Hypercalcemia), Decreased Blood Pi (Hypophosphatemia)
- DIFFERENT from Primary Hyperparathyrodisim by:
a) Decreased Bone Formation
b) Decreased PTH Levels
c) Decreased Vitamin D (In Cancer, Vitamin D Levels are normally suppressed)
TREATMENT:
1) FUROSEMIDE (Inhibits Renal Ca2+ Reabsorption and Increased Ca2+ Excretion)
2) ETIDRONATE (Inhibitor of Bone Resorption)
Humoral Hypercalcemia of Malignancy Hormone Levels
PTH
- Decreased
Ca2+
- Increased
Pi
- Decreased
Vitamin D
- Decreased
Familial Hypocalciuric Hypercalcemia
- AUTOSOMAL DOMINANT DISORDER
CAUSE:
- Mutations that INACTIVATE CaSR in Parathyroid Glands and Parallel Ca2+ Receptors in the ASCENDING LIMB OF THE KIDNEY
RESULTS IN:
- DECREASED Urinary Ca2+ Excretion (HYPOCALCIURIA)
- INCREASED Serum [Ca2+] (HYPERCALCEMIA)
Familial Hypocalciuric Hypercalcemia Hormone Levels
PTH:
- Normal or Increased
Serum Ca2+:
- INCREASED
Urine Ca2+:
- DECREASED
Pi:
- Normal
Vitamin D:
- Normal
Pathophysiology of Vitamin D: Rickets- Osteomalacia
1) IMPAIRED Vitamin D Metabolism
- Dietary Deficiency of Vitamin D
- Vitamin D Resistance
a) Deficit in Synthesis of Active Vitamin D (Absence of 1 ALPHA HYDROXYLASE)
b) Mutations Affecting Vitamin D Receptor
2) GI Disorders, Chronic Renal Failure, and Pi Depletion can lead to Pathophysiological Changes in Vitamin D Metabolism
3) RICKETS (Children)
- Insufficient amount of Ca2+ and Pi are AVAILABLE to Mineralize Growing Bone
- Characterized by Growth Failure and Skeletal Deformities
4) OSTEOMALACIA (Adults)
- New Bone FAILS to Mineralize
- Characterized by BENDING and SOFTENING of Weight Bearing Bones
Pathophysiology of Vitamin D: Rickets Congenital Disorders
1) Pseudovitamin D- Deficient Rickets or Vitamin D- Dependent Rickets TYPE I:
* DECREASED 1 ALPHA HYDROXLASE***
2) Psuedovitamin D- Deficient Rickets or Vitamin D- Dependent Rickets TYPE II:
* ** DECREASED VITAMIN D RECEPTOR*****
Rickets- Osteomalacia Hormone Levels
PTH:
- Increased (Secondary)
Ca2+:
- Normal or decreased
Pi:
- Decreased
Urine:
- Increased Pi
- Increased cAMP
Vitamin D:
- DECREASED!!!!!!!
Bone:
- Osteomalacia
- Increased Resorption
Treatment for Rickets- Osteomalacia
1) Vitamin D2 (Ergocalciferol) or D3 (Cholecalciferol)
2) Ca2+
3) Sunlight
4) 1,25 - (OH)2 - D3 (Calcitriol)
Osteoporosis
TIME DEPENDENT CHANGES IN BONE MASS:
a) MALES:
- Bone Mass starts to decline around 40 years old and there is a SMALL SLOPE of decline
b) FEMALES:
- Bone Mass starts to decline a little earlier and there is a STEEP SLOPE of Decline, especially around 50 years old
Treatment for Osteoporosis
1) ANTIRESORPTIVE THERAPY:
- Bisphosphonates
- Estrogen
- SERMs (RALOXIFENE, TAMOXIFEN)
- Calcitonin
- RANKL Inhibitors (DENOSUMAB)
2) ANALBOLIC THERAPY
- PTH!!!!!
Regulation of Ca2+ and Pi Metabolism by GONADAL and ADRENAL Steroid Hormones
- ESTRADIOL-17 Beta stimulates Intestinal Ca2+ Absorption and Renal Tubular Ca2+ Reabsorption
- ESTRADIOL- 17 Beta os also one of the MOST POTENT Regulators of Osteoblast and Osteoclast function
a) ESTROGEN promotes SURVIVAL of Osteoblasts and APOTOSIS of Osteoclasts; Favoring BONE FORMATION over Resorption - Adrenal Glucocorticoids (Ex: Cortisol) promote bone Resorption and Renal Ca2+ Wasting and INHIBIT Intestinal Ca2+ Absorption
a) Patients treated with HIGH Levels of a Glucocorticoid (Ex As an Anti-inflammatory and Immunosuppressive Drug) can develop Glucocorticoid-Induced OSTEOPOROSIS
In General Hypoparathyroidism
SYMPTOMS of HYPOPARATHYROIDISM:
- Tetany, Convulsion, Parathesias, Muscle Cramps
- Decreased Myocardial Contractility
- First Degree HEART BLOCK
- Central Nervous System Problems, including Irritability and Psychosis
- Intestinal Malabsorption
- Low Serum Calcium concentration; High Serum Phosphate Concentration
In General Hyperparathyroidism
- Kidney Stones
- Osteoporosis
- Gastrointestinal Disturbances, Peptic Ulcers, Nausea, Constipation
- Muscle Weakness, Decreased Muscle Tone
- Depression, Lethargy, Fatigue, Mental Confusion
- Polyuria
- HIGH SERUM CALCIUM CONCENTRATION; LOW SERUM PHOSPHATE CONCENTRATION (In Most Cases)
