Parathyroid

Parathyroid Gland

Hi, in this post we’ll be taking a look at the parathyroid gland which plays an important part in the regulation of calcium (Ca) and phosphorus (P) balance within the body. We’ll take a look at where calcium, phosphorus and magnesium are stored in the body as well as the role of the kidneys, digestive tract, bone and skin in maintaining calcium balance. In addition, we’ll discuss the anatomical structure of the parathyroid as well as the major physiological actions of parathyroid hormone (PTH). We’ll discuss the factors which affect the secretion of PTH and calcitriol and the process by which calcitriol is synthesised. We’ll also talk about calcium sensing receptors and a few disorders that are involved with calcium regulation.

Structure of the Parathyroid

Four parathyroid glands are found in mammals and they consist primarily of chief cells. In dogs and cats two external glands are present outside the thyroid and two internal glands are present inside the thyroid. The cells of the parathyroid are arranged into dense cords or nests around abundant capillaries. This provides the products of these cells easy access to the bloodstream.

 

Location of Storage Sites

Ninety-nine per cent of all Ca2+ in the body is found in bone in the form of hydroxyapatite crystals. Some Ca is also found in the extracellular fluid (the interstitial fluid and blood plasma) as ionized Ca (iCa, which is biologically active), complexed with other ions, and bound to proteins. Intracellularly, Ca is found mainly in the mitochondria and sarcoplasmic reticulum.

Eighty-five per cent of total P is stored in bone in the form of hydroxyapatite. Phosphorus is also found in the extracellular fluid as inorganic phosphates as well as in the intracellular fluid in its organic form (eg. Enzyme, phospholipids, ATP etc.).

The majority of magnesium is stored in bone, muscle and other soft tissue while less that 1% is present in the extracellular fluid and plasma.  

Calcium Balance

Kidneys, Digestive Tract, Bone and Skin

The plasma calcium concentrations are regulated by the kidneys, digestive tract, bone and skin. Calcium is added to the plasma by absorption from the digestive tract, resorption (mobilisation) of bone and reabsorption of calcium at the kidneys. Calcium can be removed from the plasma by calcification of bone and filtration at the kidneys.

PTH, Calcitriol and Calcitonin

In addition to the body systems described above, three hormones regulate calcium balance. These are parathyroid hormone (PTH), calcitriol (also called 1, 25-(OH)₂D₃), and calcitonin. The most important regulator of calcium and phosphorus in the extracellular fluid and blood is PTH.

PTH increases plasma calcium levels by:

• Stimulating the resorption of bone. Osteoblasts (which are responsible for laying down new bone) have surface proteins (RANKL) which bind to a receptor (RANK) on osteoclasts (responsible for breaking down bone) causing them to be activated. Osteoblasts prevent the activation of osteoclasts by secreting OPG which blocks this binding. PTH increases the synthesis of RANKL and decreases the amount of OPG, this leads to increased osteoclast activation which causes bone to be resorbed.
• Stimulating calcium reabsorption in the ascending loop of Henle and distal tubules of the kidneys. PTH also inhibits the reabsorption of phosphate in the proximal and distal tubules and this helps to maintain the correct Ca:P ratio during hypocalcaemia. 
•  Stimulating the activation of calcitriol in the kidneys. It does this by increasing the hydroxylation (and activation) of 1, 25-(OH)₂D₃ in the proximal tubule. This promotes the absorption of calcium in the GIT, reabsorption of calcium at the kidneys as well as bone resorption.

Calcitonin lowers plasma levels of calcium and phosphorus by impairing osteoclast-mediated bone resorption and by decreasing renal reabsorption of C and P. Calcitonin secretion is directly determined by the levels of Ca in the blood, high Ca = high calcitonin.

Regulation of PTH and Calcitriol

The major regulator of PTH secretion is the concentration of iCa in the plasma. A drop in iCa in plasma stimulates PTH release and this is mediated by Calcium-Sensing receptors (CaSR). Although a rise in serum Ca decreases PTH secretion it will never halt PTH secretion completely. Thus the body is better equipped to deal with hypocalcaemia than hypercalcaemia because PTH levels can be increased to deal with low calcium more than they can be decreased to deal with excess calcium. Factors other than Ca concentrations can also affect the secretion of PTH, this includes:

1.       1,25(OH)₂D₃: Calcitriol supresses gene transcription which reduces PTH synthesis but this is overridden by hypocalcaemia.

2.       Phosphate: High P concentrations stimulate the secretion of PTH. This is because it directly lowers plasma iCa²⁺ through the formation of calcium phosphate

3.       Magnesium: Hypermagnesemia reduces PTH secretion.

Calcitriol

A vitamin D precursor, 7-dehydrocholesterol is converted to vitamin D3 in the presence of sunlight and is released into plasma. Vitamin D3 can also be absorbed from the diet. Vitamin D3 then undergoes the unregulated conversion to 25(OH)D₃ in the liver which is then released into the plasma. This substance then undergoes the regulated conversion to 1,25(OH₂)₃D_3, in the proximal convoluted tubule of the kidney and is also released into the plasma. This is regulated by calcium and PTH plasma concentrations. A low calcium concentration causes more PTH to be released which stimulates this conversion. This causes the reabsorption of Ca in the kidneys and gastrointestinal tract and leads to an increase in plasma Calcium concentrations.

Disorders of Calcium Regulation

Hypocalcaemia

Hypocalcaemia may be a result of decreased bone resorption, as well as reduced GIT and renal absorption of calcium. The body attempts to maintain near-normal serum calcium and phosphate levels, this results in:

•   High PTH and 1,25-(OH₂)D₃ 
•  Increased bone resorption leading to osteopenia (termed osteoporosis in humans) 
•  Increased intestinal absorption of Ca 
•  Decreased fractional excretion of Ca in the kidney 
• Increased fractional excretion of P in the kidney.

Milk Fever in Dairy Cows

This is a metabolic disorder of dairy cows which occurs close to the time of calving. This is due to the extremely high calcium requirements of the developing calf and early lactation. Thus, feed management during the two weeks before calving is critical in order to prevent this condition.

Milk Fever causes agitation, excitement and muscle tremors in the animal. This then causes the animal to stagger and take up a ‘sitting’ position, after which the cow may lie flat on its side. This unfortunately may lead to circulatory collapse, coma and death.

Hypocalcaemia in Small Animals

Hypocalcaemic tetany (eclampsia) is common in small dog breeds which become pregnant with large litters. It occurs between 1-3 weeks after pregnancy due to the loss of calcium during lactation or poor diet. It results in seizures, trembling and stiffness in the animal.

Renal failure is also a common cause of hypocalcaemia in dogs as failure causes an inability to synthesise 1,25(OH₂)D₃.

Nutritional Secondary Hyperparathyroidism

This condition is associated with a diet which is low in calcium and/or high in phosphate and results in increased PTH secretion which leads to osteopenia of long bones and vertebrae. It is most common in young, growing animals particularly in large and giant breeds.

That’s all from me for this post, see you next time :)