Gland: Parathyroids

THE PARATHYROIDS

Located on the posterior portion of the thyroid are four-five parathyroid glands weighing 120 grams total, with an ellipsoidal shape having the dimensions of 6x5x2 millimeters. The blood supply for the parathyroids is the inferior thyroid artery. The chief cells, which are the major cells of the parathyroids, synthesize and secrete parathormone (PTH) (which is 84 amino acid’s long) that comes from a pre-proparathormone, which is 110 amino acids long.
Though calcium is the major factor controlling the secretion of PTH, secretion of newly synthesized PTH is from preformed pools of PTH, where cAMP only stimulates these pools. cAMP is the major regulator of PTH secretion. Beta-androgenic catecholamines, dopamine, secretin and prostaglandin E can activate adenylate cylclase and increase cAMP, thereby stimulating PTH regulation.
The basic function of PTH is to control calcium concentration in the extracellular fluid (ECF). Parathyroid hormone, calcitonin and calciferous are the principle calcitrope hormones. Sodium, calcium, and potassium play a central role in the transmission of information between cells.

Phosphates act as:
• Cytoplasmic buffers
• Participate in energy exchange
• Makeup membranes and nucleic acids

The bulk of calcium, phosphates, and magnesium in the body are found in the skeleton. RDA’s of calcium is between 8-1200 mgs, for magnesium 4-600 mgs and 8-1200 mgs for phosphate. Less than 2% of calcium, magnesium and phosphates are found in the plasma and extracellular fluid and are controlled in narrow limits. Steady states of calcium, magnesium and phosphorus approximate urine loss against intestinal absorption and skeletal mineral apposition against mineral absorption. Magnesium in the cells is complexed to phosphate, citrates and anions such as ATP, AMP, and ADP (such as MgATP2).
Phosphates are covalently incorporated into proteins, lipids, and nucleic acids. Many enzymes go thru dramatic shifts in activity via phosphorylation and dephosphorylation.
Ionized cellular calcium regulates secondary cell messengers. Calcium can increase in a cell due to electrical impulses, hormones, and intracellular signals. Calcium also interacts with proteins such as protein kinase C, and ion channels found in plasma membranes and the sarcoplasmic reticulum.
Parathormone levels elevate cell calcium levels in the renal tubules and the osteoblasts. Calcium is transported from the cytoplasm by exchange with sodium. Contracted striated muscle relaxes with rapid removal of calcium from the cytoplasm into the sarcoplasmic reticulum. Plasma membranes undergo many complex interactions with cellular calcium via membrane permeability and pump activity.

In erythrocytes, cellular calcium increases potassium permeability. Mitochondria contain most of the intracellular calcium. There are many cytoplasmic enzyme changes via calcium such as adenylate cylclase, guanylate cylclase, cAMP, ATPase and protein C kinase. Since calcium can regulate contractile proteins, it can affect striated muscle, secretory granule contraction, exocytosis, mitotic spindle function and ciliary beating.
Calcium concentrations can be reduced quickly via repetitive nerve stimulation. Albumin accounts for 70% of the protein binding of calcium. Magnesium bonds to the same site on the albumin molecule as calcium, but with a lower affinity, thereby having more magnesium in a diffusible form. Magnesium is also affected just the way calcium is to parathormone, and to a lesser degree calcitonin.
70 % of phosphates are bound to phospholipids and phosphoproteins and are also affected in and out of plasma compartments by parathormone, calcitonin, and calciferols.
PTH enhances phosphate secretion and inhibits sodium reabsorption in the proximal tubules. PTH stimulates both bone formation and reabsorption (catabolism and anabolism) via influencing osteoclasts, osteoblasts, and osteocytes. PTH enhances synthesis of hyaluronate and inhibits citrate decarboxylation and collagen synthesis while it increases alkaline phosphatase levels.
Other affects of PTH include changes in blood flow, mitosis of lymphocytes, enhanced lipolysis and increased gluconeogenesis from the liver and kidney. PTH reacts with specific receptors on the bone and kidney (renal cortex) activating adenylate cylclase and intracellular messenger cAMP
According to Guyton’s Physiology on the physiology of calcium and phosphate “phosphates act as buffers, participate in energy exchange, and are an essential component of membranes and nucleic acids. 70 % of phosphates are bound to phospholipids and phosphoproteins.”
Phosphates do not affect PTH or calcitonin (CT) levels, but PTH and CT affect phosphate levels. The function of vitamin D and the formation of bone and teeth are all tied together in a common system, along with the two regulatory hormones parathyroid hormone (parathormone), calcitonin and the calciferols. In mammals, the bulk of calcium, phosphates and magnesium are found in the skeleton as hydroxyapatite. Less than 2% are found in the extracellular fluid.
Plasma calcium is used for clotting and kinin formation, regulates plasma membrane potential and exocytosis. As stated above, albumin accounts for 70% of the bound calcium. Magnesium also binds to albumin, and since it has a lower specificity for the receptors, it creates more free magnesium in the plasma. Calcium, magnesium, and phosphates continuously enter the plasma via the kidneys (intestinal brush borders) and the ruffled border of bones.
Calcium, phosphates, and magnesium are depressed in vitamin D deficiencies. Phosphates are reabsorbed by the proximal convoluted tubules due to PTH, and PTH also absorbs magnesium and calcium from the distal tubules. Calcium is poorly absorbed in the intestinal tract, as are most other bivalent cations. Calcium absorption can be dramatically affected by vitamin D, which has a potent effect on increased calcium absorption in the intestinal tract. In fact calcium, magnesium and phosphates are depressed in vitamin D deficiencies and increased with vitamin D excess. Calcium absorption is also increased by dietary sugars.
The D vitamins (calciferols) are steroid molecules of 4 rings. Calciferols are absorbed in the chylomicrons of the small intestines (60-90%) and are bound to alpha globulins. Vitamin D is also stored in the adipose tissue. It is not actually vitamin D, but a vitamin D compound that is formed between the liver and the kidneys, known as 1,2,5-dihydroxycholecalciferol. This 1,2,5-dihydroxycholecalciferol is also stimulated by parathyroid hormone. Another vitamin D compound that is important is D3 (cholecalciferol), found in the skin.

BONE FORMATION

Skeletal tissue consists of an extracellular matrix 55% organic and 45% inorganic and cells. The purpose on the skeletal system is to regulate the distribution of inorganic compounds, such as calcium, for the remodeling and the formation and reabsorption of the matrix.
There are 3 types of cells
1. Osteoblasts-derived from pre-osteoblasts from the mesenchyme. They are cuboid in shape, have a lot of Golgi apparatus for collagen processing, and lots of alkaline phosphatase. Osteoblasts are located in the bone-forming surface and are responsible for elaborating organic compounds from the extracellular matrix and the mineralized bone. The unmineralized matrix forms the osteoid zone and is separated from the mineralized bone via the calcification front. Osteoblasts form bone by the release of alkaline phosphatase, which increases the concentration of phosphate into the bone matrix.

2. Osteocytes-once osteoblasts, they are surrounded by an organic matrix and are now called osteocytes.

3. Osteoclasts-are also found on the bone surface. They are multinucleated, highly mobile moving along the bone surface reabsorbing bone. Osteoclasts break bone down. The cytoplasm contains abundant mitochondria, vacuoles, and lysosomes containing acid hydrolases such as carbonic anhydrate. Other cells found in bone are endothelial cells, fibroblasts, preosteoclasts, and preosteoblasts. Other inorganic components that make up the inorganic matrix are calcium, phosphate in a crystalline structure known as hydroxyapatite, with fluorine, sodium, potassium, magnesium and carbonate.
80% of the skeletal mass is made of cortical (compact) bone (long bones). Cortical bone is composed of packed osteons (haversian systems) surrounding a central canal, and volkmann canals, which radiate from the central canal connecting neighboring osteons to form an anatomizing network for blood and lymph. 20% is trabeculae bone (spongy) (vertebra, the ends of long bones and flat bones.) In trabeculae bone, lamellas are arranged in longitudinal bundles and anastomose with the marrow cavity. Please note that the surface area of trabeculae bone is 5 times that of compact bone.
Bone formation is controlled by osteoblast differentiation, proliferation, matrix formation and mineralization (by alkaline phosphatase cleaving phosphate groups.)
Bone contains many growth factors such as:
• Transforming growth factor B produced by the osteoblasts, which stimulate mitogenesis and collagen synthesis
• IGF 1 and IGF 2
Bone proteins consist of 13 forms of collagen, osteonectin (a carbohydrate containing protein), osteocalcin, osteopontin (produced by osteoblasts) and proteoglycans (glycosaminoglycans), which are controlled by autocrine, paracrine and systemic hormone regulation. Osteocalcin is a protein making up 1-2% of the total bone protein and depends on vitamins D, K, and C.

PROMOTERS OF BONE FORMATION
• INSULIN
• IGF 1 and 2
• ESTROGENS/ANDROGENS
• GROWTH HORMONE
• THYROID HORMONE
• PTH

PROMOTERS OF BONE REABSORPTION
• PTH
• Interleukin 1
• Prostaglandins
• Thyroid hormone
• Epidermal growth factor
• Vitamin A
• Tumor necrosing factor

INHIBITS BONE REABSORPTION
• Calcitonin
• Phosphate
• Glucocorticoids

FORMATION OF THE CALCIFEROLS

7-DEHYDRO CHOLESTEROL OR ERGOSTEROL

PLUS LIGHT

LUMSTEROL PREVITAMIN D TACHYSTEROL

VITAMIN D2 D3
(CHOLECALCIFEROL) (ERGOCALCIFEROL)

DIHYDROTACHYSTEROL

D3 is formed through irradiation of 7 dehydrocholesterol. Dihydroxycholecalciferol lines the intestinal epithelium, absorbing large quantities of calcium when needed in the blood or bone. On the other hand, phosphorus is easily absorbed, unless there are large quantities of calcium that combine with phosphate creating an insoluble calcium phosphate compound that is excreted from the bowel. Ninety percent of all calcium loss is from the bowel. Ten percent is excreted in the urine. The ten percent that is excreted in the urine is controlled by parathyroid hormone, which also causes the excretion of phosphorus.

Plasma calcium is found in three different forms:
• 40% is combined with plasma proteins
• 10% is bound to phosphates and is not usable
• 50% is in the ionized and diffusible state necessary for heart function, bone formation, and nervous system control.

Phosphates exist in two states HPO4, HPO4. When the pH of the extracellular fluid becomes acid, there is an increase in HPO4 and a decrease in HPO4, with the reverse also being true. Phosphorus levels can dramatically change without affecting function. On the other hand, increased amounts of calcium in the blood can cause central nervous system depression. Decreased calcium in the blood can lead to tetney.

Parathormone controls calcium ion concentration in the extracellular fluid by controlling calcium absorption in the intestines, excretion via the kidneys (increases distal tubular reabsorption of calcium and magnesium) and release of calcium from the bones.
Magnesium can exert control over PTH retention.
Calcitonin (CT) is secreted by the parafollicular cells of the thyroid gland as mentioned above, has the opposite effect of parathormone. Although the effect is much weaker than parathormone, there is still that balance necessary to be maintained.
Calcium also stimulates the secretion of CT, as does beta androgenic catecholamines, gastrin, and cholecystokinin. CT decreases alkaline phosphatase, pyrophosphatase activity, and hydroxyproline production. CT inhibits calcium reabsorption from bone.
Therefore parathormone, which is a polypeptide (110 amino acids long), together with calcitonin (32 amino acid’s long), regulates the calcium-phosphorus ratio. If you lack calcium/phosphorus in the blood, then parathormone will shift them out of the bone and decrease excretion from the distal kidney tubules.

Bone is composed of:
• 90-95% collagen (protein)
• 5% ground substance, which is composed of fluid, proteoglycans, chondroitin sulfate and hyaluronic acid.
• 5% bone salts composed of calcium and phosphorus. The major crystalline salt is hydroxyapatite (CA10 (PO4) 6 (OH) 2), along with other bone salts such as magnesium, sodium, carbonate, uranium, plutonium, strontium and K.

PHOSPHORUS AND CALCIUM INVOLVEMENT IN DIGESTION
Phosphorus is also the regulator of the stomach. Phosphorus regulates the amount of HCl and pepsin in the stomach, which controls carbohydrate metabolism via the process of phosphorylation. Phosphorylation is the process that hydrogenates the carbohydrate, which alters the pH for glycogen storage in the liver. Oxygen, on the other hand, oxidizes carbohydrates for immediate use.
The thymus, which will be covered later, assists the parathyroids in the process of phosphorylation. If the phosphorus in the stomach is too low, then the carbohydrate cannot be hydrogenated and the HCl content of the stomach increases, causing an acid stomach. When the phosphorus content is too high, there is a depletion of HCl content in the stomach. This creates an alkaline stomach.
Calcium is the regulator of the small intestines. Calcium, along with B12 and folic acid, attach to lipoproteins so that they can be polarized through the intestinal wall, via magnesium. At the proper time, the calcium will be severed from the lipoprotein when needed for hormone, enzyme, and antibody formation. At that point, the calcium will be released back into the body. The following tests can be used to assess parathyroid function:

1. CALCIUM

2. PHOSPHORUS