Parathyroid Hormone
Calcium Reabsorption from Distal Nephron.
(top diagram) The illustration above represent a renal nephron. Note that ≈90% of the total calcium reabsorbed by the kidneys occurs in the Proximal Tubule. This fraction of filtered Ca++ is NOT hormonally regulated and is, therefore, PTH Independent.
In response to hypocalcemia, Parathyroid Hormone stimulates Ca++ mobilization from bone into ECF. Ca++ is exchanged between bone and ECF through two basic mechanisms.
Bone Remodeling. Hydroxyapatite (top center) is continuously metabolized through a constant cycle of Degradation & Resynthesis termed Bone Remodeling that involves 3 bone cell types: Osteoblasts (middle right) promote CaPO4 deposition & mineralization into the hydroxyapatite and are primarily responsible for Bone Synthesis. As shown above, osteoblasts form a continuous sheet along the surface of newly forming bone within Lamellae. Osteocytes (bottom left) are osteoblasts that become entrapped within Lacunae (middle left) when crystallized bone salts form around them. Long processes extend from osteocyte to osteocyte as well as with osteoblasts via Canaliculi (bottom right). Osteoclasts (top left) secrete hydrolytic enzymes that degrade existing hydroxyapatite in a process termed Bone Resorption. Osteoclasts sweep over the surface of bone, dissolving protein matrix and crystals. Normally, bone Resorption & Synthesis are balanced in healthy mature bone to maintain bone size. However, under conditions such as Chronic Hypocalcemia, mobilization of soluble bone salts (see above) becomes limiting and Net Hydroxyapatite Resorption occurs in order to supply the needed Ca++ to maintain normal ECF Ca++ levels. Recall that bone integrity is always sacrificed to maintain the ECF [Ca++]. Because of the extended time required to alter the remodeling equilibrium, this is a Slowly Responding mechanism that maintains ECF calcium homeostasis. The specific actions of PTH that result in these mechanism is explained next.
Calcium homeostasis - hypocalcium
Ca++ homeostasis involves the actions of Parathyroid Hormone, 1,25-Dihydroxycholecalciferol & Calcitonin. Acute & chronic perturbations in ECF [Ca++] set into motion hormonal actions at regulatory sites in Bone, the GI Tract & Kidneys, which function to normalize ECF [Ca++]. Actions are summarized above in response to a HYPOCALCEMIC challenge and in the next figure to a Hypercalcemic challenge. Rapid Responses (outer right arrows). PTH secretion (top) occurs in response to even very small decreases in [Ca++]. Rapid PTH actions include (1) Inhibition (-) of Renal Ca++ Excretion from the distal tubules & (2) Stimulation (+) of Bone Osteolysis (soluble bone salt). Some renal augmentation by 1,25(OH)2D3. These actions are initiated within Minutes-Hours after onset of hypocalcemia, but are usually only able to compensate for mild & brief hypocalcemia episodes. Slow Responses. (leftward arrow) Increased Ca++ Absorption from GI Tract is stimulated by increased activation of 1,25(OH)2D3. in the kidneys by PTH . (center arrow from PTH ) Increased Bone Resorption occurs mainly in response to PTH with support from 1,25(OH)2D3. These actions are initiated after ≈24 Hours of hypocalcemia. Bone actions may last for months or years, but with constant bone loss if left untreated.
Example of rationalizing the pathophysiology of Secondary Hyperparathyroidism...Chronic Kidney Failure
Decreased renal calcium reabsorption leads to low serum Ca++ Decreased renal phosphate excretion leads to high serum phosphate, which worsens hypocalcemia through increased CaPO4 formation and suppresses vitamin D activation. Decreased renal vitamin D activation leads to deficiency that exacerbates hypocalcemia All outcomes lead to compensatory hyperPTH secretion. FGF-23 effects not discussed.
HYPERCALCEMIA i
HYPERCALCEMIA is rarely observed pathophysiologically. However, one possible scenario involves an individual who has subsisted on a prolonged Low Calcium Diet and then suddenly ingests a High Ca++ Meal as depicted above. Prior to this meal, Rapid & Slow Responses to Chronic Hypocalcemia have resulted in HIGH PTH & 1,25(OH)2D3 levels, causing elevated Bone Osteolysis & Resorption and maximal Intestinal Ca++ Absorption & Renal Ca++ Reabsorption. When the high calcium meal is consumed under these circumstances, ECF [Ca++] rapidly increases (Hypercalcemia), initiating the following compensatory regulatory processes: Rapid Suppression. PTH secretion decreases immediately, increasing Renal Ca++ Excretion & Decreasing Bone Osteolysis. Slow Suppression. In contrast to rapid PTH actions, Several Hours are required for PTH stimulated renal 1,25(OH)2D3 production and osteoclast activity to diminish. Many more hours (10-20 hours) are required to suppress 1,25(OH)2D3 actions on all tissues due to its relatively long half-life. Much later, Calcitonin secretion (top right) may be necessary to directly Inhibit Osteoclast Activity, which more rapidly slows Ca++ influx into the ECF.
Parathyroid hormone (PTH) is secreted by the Parathyroid Glands, which adhere to or are imbedded within the posterior surface of the Thyroid Glands.
Humans typically have four parathyroid glands, which are flattened and elipsoid glands measuring about 6 mm in length and weighing less than 150 mg. They are well vascularized and derive their circulation from the inferior thyroid arteries. Parathyroid glands are comprised of two main cell types: Chief Cells secrete PTH and are arranged in clusters typical of peptide hormone secreting cells. Chief cells are the predominant parathyroid cell type. Oxyphil Cells have no known function, but may be a type of Degenerating Cell. They are larger than chief cells and appear singly or in small groups. Few oxyphil cells are observed prior to puberty but increase with age.
Phosphate Excretion from Proximal Tubule.
In contrast to Ca++ regulation, PTH powerfully Inhibits tubular reabsorption of Phosphate (PO4) and thus increases the urinary PO4 Excretion. This effect is exerted mainly at the Proximal Tubule where most PO4 reabsorption occurs. PTH apparently decreases the abundance of Na+-PO4 Co-Transporters along the proximal tubular cells by stimulating their translocation to intracellular stores.
Laboratory Diagnosis.Rickets
Laboratory Diagnosis. In addition to decreased 1, 25 (OH)2-D3 levels, PTH is elevated as a compensatory response to hypocalcemia (2∞ Hyperparathyroidism). Hypocalcemia or Eucalcemia. Plasma [Ca++] is usually only slightly depressed (↓) or even normal (↔) because PTH is capable of maintaining calcium homeostasis through increased bone resorption and renal Ca++ reabsorption. Severe Hypophosphatemia. By contrast, plasma [PO4] is greatly depressed (↓↓) primarily because compensatory increases in PTH activity in response to hypocalcemia causes increased phosphate excretion from the proximal tubules. This underscores the relatively weak regulatory system that maintains phosphate homeostasis. The latter two manifestations assist in distinguishing this condition from Primary Hyperparathyroidism. Also see laboratory differential diagnosis section of Hypothalamus-Pituitary section. Alkaline Phosphatase may also become elevated as a consequence of increased bone resorption and turnover.
Calcium & Phosphorus metabolism and regulation are closely linked.
Normal adults possess a total of ≈600 grams of phosphorus. About 85-90% (540 gms) is found complexed with calcium in hydroxyapatite bone crystals. In addition, a lower amount (58 gms) exists in intracellular fluid or is incorporated cellularly into tissue cell membranes & cell components (combined = ICF Ca++ ). The remainder (600 mg) is found extracellularly (ECF) either as free ion, in complex with cations (e.g. calcium), or bound to plasma proteins. As summarized above, maintenance of daily phosphorus balance is also similar to that of calcium. Phosphorus intake is ≈1500 mg/day. Balance is maintained through regulated actions of the GI Tract & Kidneys. An important difference is that although hormonal regulation occurs, Phosphate is Not as Tightly Controlled Hormonally compared to calcium. Consequently, phosphorus level varies more under influences such as diet, age, & gender.
Indirect Stimulation of Osteoclast Activity by PTH
PTH stimulates bone resorption by osteoclasts, but it does so indirectly. Receptors for PTH are located on osteoblasts, which then signal to bone marrow-derived osteoclast precursors to stimulate their fusion, differentiation and activation. Osteoclast precursors express a cell-surface receptor known as RANK (Receptor Activator of Nuclear factor-Kappa B). Osteoblasts express RANKL (RANK Ligand) on the extracellular surface of their plasma membrane. When they are stimulated by PTH, osteoblasts up-regulate expression of RANKL, which binds to RANK, activating signaling pathways that promote osteoclast differentiation and survival. Osteoblasts also express a secreted factor called Osteoprotegerin. As its name implies, osteoprotegerin "protects bone" by preventing bone resorption. Osteoprotegerin works as a decoy receptor for RANKL: it binds RANKL and therefore prevents binding to RANK and stimulation of osteoclastogenesis. The ratio of osteoprotegerin:RANKL produced by osteoblasts will determine the extent of bone resorption.
Vitamin D Activation
PTH stimulates the renal activation of Vitamin D, which is essential for the absorption of ingested Ca++ & PO4. This will be discussed in more detail later.
Three hormones are primarily involved in the regulation of calcium & phosphorus balance:
Parathyroid hormone (PTH) is a Protein Hormone secreted by the Parathyroid Glands. PTH acts directly on Bone and the Renal Tubules and indirectly on the GI Tract to Increase plasma [Ca++] and to Decrease plasma [PO3-]. 1,25(OH)2-Cholecalciferol (Vitamin D; Calcitriol) is a Steroid-like (Sterol) Hormone that acts mainly on the GI Tract, and less potently on Bone and the Renal Tubules to Increase plasma [Ca++] and [PO3-]. Calcitonin is a Protein Hormone secreted by Parafollicular C-Cells in the Thyroid Gland. Calcitonin acts mainly on bone to Decrease plasma [Ca++] The actions and properties of each of the these hormones will be discussed in detail.
what happens minutes after hypocalcemia
Parathyroid hormone actions are responsible for the Rapid Phase of Ca++ mobilization from bone, which begins within Minutes after the onset of hypocalcemia and can persist for Hours. (left) PTH is thought to increase (↑) Ca++ Permeability of the Osteocyte membrane that separates the Bone Fluid (ECF) from the Soluble Bone Salt compartment (top left inset). This action increases Ca++ flux into osteocytes, driven by a steep concentration gradient from bone fluid into the cell. Increased Ca++ uptake by osteocytes lowers bone fluid [Ca++], which shifts the equilibrium toward Soluble Bone Salt ionization and Ca++ mobilization into Bone Fluid (bottom center). This process is termed OSTEOLYSIS. The Ca++ taken up by osteocytes is then transported via canaliculi leading to osteoblasts where it diffuses into the ECF (dashed rightward arrows) to normalize plasma [Ca++].
Primary Hyperparathyroidism:
Primary Hyperparathyroidism: Basic disorder is Excess PTH secretion due to parathyroid gland dysfunction. Parathyroid Adenoma (top right) accounts for 80-85% of cases. Most clinical features related to primary development of Hypercalcemia. Hypercalcemia Effects. Hypercalcemia causes Skeletal Muscle Weakness & Fatigue as well as abnormal electrical activity of the heart (e.g., Bradycardia). Contractile impairment suppresses GI motility, resulting in Nausea, Constipation & Lack of Appetite. Impaired muscular contraction is caused by decreased membrane Na+ permeability that decreases depolarization sensitivity (i.e., hyperpolarization due to increased cation charge. Decreased Na+ permeability, is attributed to increased Ca++ binding to Na+ channels, which increases positive charge on the channel and decreases its sensitivity to voltage changes and results in hyperpolarization. As discussed later, hypocalcemia causes the opposite effects on muscle contractile state (i.e., Tetany). Sluggish neural activity can cause development of CNS Depression. Bone Effects. Enhanced Bone Remodeling, but Net Bone Resorption due to enhanced Osteoclast activity. Results in greatly Weakened Bones with severe Bone Pain (osteitis fibrosis cystica) that greatly increases the potential for bone fracture. Renal Effects. Mild hyperparathyroid patients commonly develop Kidney Stones, which are calcium phosphate crystals that precipitate in the kidneys as a result of the proportionate increase in renal calcium and phosphate filtration. Laboratory Diagnosis. Typical laboratory findings diagnostic of primary hyperparathyroidism are summarized above (bottom right text box). Rationalize the findings based on the known physiological actions of PTH. What is the role of alkaline phosphatase and why would it be elevated?
Primary Hypoparathyroidismdisorder
Primary Hypoparathyroidism Basic disorder is Deficient PTH secretion due to parathyroid gland dysfunction. In contrast to hyperparathyroidism, hypoparathyroidism is rare (incidence?). Most common causes is surgical removal (e.g. Thyroidectomy). Most clinical features related to primary development of Hypocalcemia, which manifests as Neuromuscular Impairments. Clinically, the hallmark of severe hypoparathyroidism (hypocalcemia) is TETANY. This state of spontaneous tonic muscular contraction is caused by increased membrane Na+ permeability that increases depolarization sensitivity. Increased Na+ permeability, is thought to be the result of decreased Ca++ binding to Na+ channels, which apparently decreases the positive charge on the channel and increases its sensitivity to voltage changes. Involuntary tetanic muscle contractions are painful. The hands are typically involved but other muscle groups are affected. The principal manifestations in the hands usually begins with adduction of the thumb, followed by flexion of the wrist, forming the characteristic "TROUSSEAU'S SIGN" (bottom left), which can be elicited clinically in patients as diagnostic of the condition. Laboratory Diagnosis. Typical laboratory findings diagnostic of primary hypoparathyroidism are summarized above (bottom right text box). Rationalize the findings based on the known physiological actions of PTH.
Calium in the body
The adult human body possess ≈1000 gms of Calcium, which is mostly distributed in Bone. However, smaller but functionally important Extracellular & Intracellular pools also exist. Bone Calcium (top left text box). About 99% of total body calcium is contained in bone, primarily in the form of Hydroxyapatite crystals (Ca10(PO4)6(OH)2). Bone primarily serves to maintain Skeletal Structure, but also functions as a large Ca++ Reservoir that is stored (Bone Synthesis) or mobilized (Bone Resorption) in response to deviations in sxtracellular & intracellular Ca++ levels. Thus, bone plays an important role in calcium homeostasis. Extracellular Fluid Calcium (bottom left text box). About 0.1% of total calcium exists extracellularly in Interstitial Fluids (ISF) & Plasma. Extracellular fluid calcium is vital for Blood Clotting and maintenance of the normal electrochemical Membrane Potential. Interstitial Fluid Calcium (1.5 x 10-3 M) exists mainly as Ionized Ca++ although some is Complexed by anions (e.g. citrate, lactate, phosphate). Both forms of ISF calcium freely Diffuse through capillary membranes and equilibrate with Ca++ pools in Plasma as well as a soluble calcium pool in bone. Plasma Calcium (2.5 x 10-3 M) also exists as Ionized & Complexed Ca++. However, plasma calcium is also significantly Bound to plasma proteins (albumins & globulins), which cannot diffuse across capillary membranes. This Non-Diffusible calcium accounts for the higher [Ca++] in plasma relative to ISF. Intracellular Calcium (bottom right text box). Intracellular calcium is involved in the regulation of many important cellular processes, some of which are listed. Approximately 0.9% of total body calcium is contained intracellularly in soft tissue cells. However, intracellular calcium is Mostly Sequestered within Mitochondria & Microsomes. Only a small concentration of Ca++ is actually maintained in the Cytoplasm, which is equilibrated with ECF ionized Ca++ pools. An intracellular Bound calcium fraction also exists. NOTE: An important concept related to calcium regulation is that Hormonal Control mechanisms are primarily sensitive to deviations in Extracellular [Ca++ ] (primarily Plasma [Ca++ ]). Fluctuations in intracellular & bone calcium pools are regulated indirectly through their equilibration with the regulated ECF Ca++ pool.
Only ≈10% of filtered Ca++ reaches the Distal Tubule.
The reabsorption of this fraction is regulated by PTH and is, therefore, PTH Dependent. Thus, a limitation of PTH stimulation of renal Ca++ reabsorption is that it has a Low Capacity that saturates when the filtered calcium load becomes too high. For example, only ≈10% of the 10% of total filtered Ca++ that reaches the distal tubule can be reabsorbed even when PTH is maximally stimulated.
PTH also initiates the Slow Phase of Ca++ mobilization from bone in response to hypocalcemia.
The steps in normal Bone Remodeling are summarized above (left). Recall the cooperative actions between Osteoclast (Resorption) & Osteoblast (Synthesis) on hydroxyapatite turnover. (top right text box) PTH increases Ca++ mobilization from bone by causing net (↑) Bone Resorption through suppression of (↓) Osteoblast Activity & stimulation of (↑) Osteoclast Activity. Interestingly, osteoclasts do not possess PTH receptors and are induced indirectly via PTH stimulation of RANKL (receptor activator of nuclear factor-κB ligand) from osteoblasts, which basically allows formation of active osteoclasts. In any case, the net effect is ↑ ECF [Ca++]. Ca++ enters the ECF via the same route described for the Rapid Phase. Bone resorption is a potent mechanism for normalizing hypocalcemia. However, the response is relatively SLOW because of the delayed response of bone cells to PTH actions. Activation occurs only after many Hours or Days following the onset of hypocalcemia and Weeks-Months may be required for full develop. (bottom right text box) PTH Actions on GI Tract. Interestingly, PTH apparently has NO direct effects on either calcium or phosphate absorption from the GI tract. However, PTH acts to stimulate Vitamin D activation in the kidneys. Vitamin D actions and its relationship to PTH and calcium & phosphate homeostasis are discussed next.
Maintenance of body Ca++ pools in the ICF (top center), ECF (center), & Bone (right) compartments occurs in coordination with the
absorptive & secretory actions of the GI Tract (left) and the filtration, reabsorptive & excretory functions of the Kidneys (bottom). The average daily U.S. intake of calcium in the diet (top left) is ≈1000 mg/day (8-oz of milk = 290 mg calcium). Calcium absorbed from the GI Tract exchanges with and replenishes the various body pools (Bone, ICF, ECF). Excesses are ultimately lost in the Urine & Feces. Normal adults maintain a net Calcium Balance. That is, daily intake from the diet (1000 mg) equals daily loss in urine (100 mgs) & feces (900 mgs) such that steady-state levels within compartments are maintained. Calcium equilibrium is maintained through Hormonal Regulation of Intestinal Absorption, Kidney Reabsorption, & Bone Resorption & Synthesis (dashed arrows). NOTE: An important principle related to calcium homeostasis is that Bone Calcium Will Always Be Sacrificed to Maintain ICF & ECF [Ca++ ]. This property of calcium homeostasis is a major reason for conditions such as Osteoporosis and other bone weakening disorders related to a hypocalcemic state.
