Parathyroid Glands and Calcium Homeostasis

Learning Objectives

• Locate the parathyroid glands and describe their macro and microanatomy
• Understand the relevance of calcium and phosphate to maintain body homeostasis
• Understand the synthesis, regulation, and transport of PTH
• Describe the effects of parathyroid hormones on target tissues/organs
• Understand the role of PTH on calcitriol activation and its importance on calcium metabolism
• Understand the relationship between PTH and calcitonin and their effects on calcium and phosphate homeostasis
• Understand the symptoms of the main pathologies related to parathyroid hormones, including hyperparathyroidism/secondary nutritional hyperparathyroidism, and hypoparathyroidism

Terminology and Abbreviations

• AMP stands for Adenosine Monophosphate
• ATP stands for Adenosine Triphosphate.
• ECF refers to extra cellular fluid
• GI refers to gastrointestinal
• iCa is Ionized calcium
• PTH stands for parathyroid hormone

Parathyroid Gland - Anatomy

• Most species have two pairs of parathyroid glands
• Pigs and rats have only one pair of parathyroid glands
• The location of parathyroid glands varies between species
• Parathyroid glands are usually at the poles of the two lobes of the thyroid glands

Chemical Structure of Hormones: Protein and Peptide Hormones

• Protein and peptide hormones comprise the majority of hormones
• Examples of protein and peptide hormones include insulin, ACTH, PTH, CCK, LH, FSH, and TSH
• Protein and peptide hormones are synthesized as inactive molecules in the ER, known as pre-prohormones
• They are cleaved in the Golgi apparatus to form prohormones
• The hormones are packaged into secretory granules awaiting secretion

Parathyroid Gland Cell Types

• There are two types of parathyroid cells in the glandular tissue: chief cells and oxyphil cells
• Chief cells produce PTH (Parathormone or Parathyroid hormone)
• The function of oxyphil cells is unknown; these cells are larger than chief cells and possess oxidative and hydrolytic enzyme activity

PTH Synthesis

• Parathyroid cells are very sensitive to a decline in blood ionized calcium [iCa]
• Calcium-sensing receptors on the gland membrane surface are involved in PTH synthesis
• G-Protein coupled receptors (cAMP-PKA-gene transcription)
• A decrease in blood [iCa] (hypocalcemia) stimulates PTH release
• Normal or increased [iCa] in blood (hypercalcemia) inhibits PTH release
• Prepro-PTH is synthesized in rER and then cleaved to pro-PTH
• The "pro" portion is removed in the Golgi apparatus, and the resulting PTH is secreted by exocytosis
• PTH is metabolized by the liver and the kidneys with a half-life of 5-10 minutes

Parathyroid Gland – Calcium and Phosphate

• The main gland involved in the Calcium (Ca2+) & Phosphate (PO4) homeostasis
• Calcium and phosphate ions play a major role in physiological homeostasis
• Phosphate (PO4) acts as a buffer system
• Phosphate is a composition of the cell membrane and intracellular components, nucleic acid, Adenosine Triphosphate (ATP), and Adenosine Monophosphate (AMP)
• 85% of phosphate is found in bones, 14% intracellularly, and 1% in ECF
• Calcium is required for muscle contraction and nerve cell activity
• Calcium facilitates the release of hormones by exocytosis and enables the activation of several enzymes
• Calcium is involved in blood coagulation
• Calcium ensures the maintenance of membrane stability
• Calcium provides structural integrity to bones and teeth
• 99% of calcium is found in bones, less than 1% intracellularly, and 0.1% in ECF

Pool of Calcium

• 99% of calcium is found in bones in the form of hydroxyapatite crystals, which contain calcium, phosphate, and water
• Less than 1% of calcium is intracellular and bound to proteins within the ER or mitochondria, and increased intracellular calcium concentrations indicate increased cell activity
• 0.1% of calcium is found in ECF, which is the interstitial fluid and blood
• 50% of calcium is ionized (iCa), which is biologically active and precisely regulated
• 40% of calcium is bound to proteins, mainly albumin
• 10% of calcium is combined with other anions
• iCa is the most important pool for physiological control of calcium concentrations in the blood

Calcium: Phosphate Ratio

• High levels of plasma phosphate concentration means a rise in the fraction of Ca2+ that is complexed (bound) increases which decreases the ionized Ca2+ concentration
• If the plasma phosphate concentration decreases -> the complexed Ca2+ decreases ionized Ca2+ increases
• Maintaining the blood Ca:P ratio is essential for homeostasis

Calcium-Phosphate Metabolism

• Calcium level regulation involves controlling the movement of calcium between the extracellular fluid (ECF) and three organs:
  • Bones
  • Kidneys
  • GI tract
• Three hormones are involved in this process:
  • PTH (parathyroid hormone)
  • Active Vitamin D (Calcitriol – steroid-like molecule)
  • Calcitonin (thyroid hormone – parafollicular cells/C-cells)

PTH Actions

• The net effect of PTH is to increase calcium and decrease phosphate concentrations in ECFs
• PTH has a direct effect on bone and kidney metabolism of calcium
• PTH has an indirect effect on GI metabolism of calcium (absorption)
• This indirect effect is conducted via calcitriol

Bones

• Osteoblasts are responsible for the formation of new bone tissue, which entails bone developing and remodeling
• Osteocytes enable biomineralization (local mineral deposition at the bone matrix) and are differentiated from osteoblasts (mesenchymal stem cells)
• Osteoclasts degrade bone tissue and are differentiated from monocytes (hematopoietic stem cells)

PTH Actions – Two Direct Effects on Bone

• PTH promotes the transfer of iCa across the osteoblast-osteocyte membrane
• Osteocytes pump iCa from the fluids within bone canaliculi into the extracellular fluid, then into the blood
• PTH binds to receptors on bone osteoblast cells and stimulates the production of osteoclast-activating factor
• PTH causes activation of nearby osteoclasts
• PTH moves toward the bone and begins to digest the organic matrix, resulting in bone resorption
• PTH releases iCa and PO43- into the blood

PTH Actions - Direct Effects on Kidneys

• PTH acts on the distal convoluted tubules, increasing reabsorption of calcium
• PTH acts on the proximal convoluted tubules, decreasing renal reabsorption of phosphate
• PTH acts on Vitamin D activation by the kidneys
• Vitamin D must be transformed by the liver and kidneys to become biologically activated
• PTH stimulates the kidney enzyme 1-alfa-hydroxylase, which converts calcidiol 25(OH)D to calcitriol 1,25(OH)2D
• Vitamin D becomes an active hormone under PTH action on renal cells
• Calcitriol increases absorption of calcium by the GI tract and enhances the effects of PTH on bone metabolism of calcium

Vitamin D Metabolism

• In the presence of UV light, Vitamin D3 (Cholecalciferol) is made in the skin
• Vitamin D3 can be found in oily fish, egg yolks, and fortified food
• Vitamin D2 (Ergocalciferol) is found in fortified foods, salmon, mushrooms, and egg yolks
• The liver converts Vitamin D3 and D2 to 25-hydroxyvitamin D (Calcidiol)
• The kidney converts 25-hydroxyvitamin D to 1,25 dihydroxyvitamin D (Calcitriol) via 1-alfa-hydroxylase
• The product is the biologically active form.
• Due to its lipid nature, calcitriol is carried in plasma by transcalciferin, which is produced in the liver

PTH Actions - Indirect Effect on GI

• Calcitriol stimulates the active transport of dietary calcium across the intestinal epithelium
• Without calcitriol, most animals cannot acquire enough calcium from their diet to support normal bone structure
• An animal can regulate iCa entering the blood from its diet by regulating calcitriol
• However, hindgut fermenters (horses and rabbits) are exceptions to this rule
• These animals have intestinal mechanisms to absorb calcium all the time
• Furthermore, they regulate blood Ca2+ by increasing/decreasing urinary loss
• These animals can present chalky white-colored urine

PTH Regulation

• PTH secretion is mainly controlled by free (ionized) calcium concentration in the blood
• A decrease in [iCa] stimulates PTH secretion
• An increase in [iCa] inhibits PTH secretion

Calcitonin

• Calcitonin is produced by parafollicular cells or C-cells in the thyroid gland
• These cells are scattered throughout the body of the thyroid gland, among the follicles
• Calcitonin is synthesized as a protein hormone
• An increase in blood [iCa] stimulates calcitonin release
• Calcitonin counterbalances the effects of PTH

Calcitonin Actions

• Calcitonin reduces the movement of calcium from the bone to the ECF
  • It moves against the bone calcium pool (decreasing the action of osteocytes behind the osteoblast-osteocyte barrier)
• Calcitonin decreases bone resorption through a direct inhibitory effect on osteoclasts
• Calcitonin increases movement of phosphate from ECF into bone
• Calcitonin increases renal excretion of calcium and phosphate

Calcitonin Regulation

• Calcitonin secretion is regulated by calcium concentration in the blood
• Increased [iCa] stimulates calcitonin secretion
• GI hormones also stimulate the secretion of calcitonin

Calcium Metabolism

• PTH increases reabsorption in the kidneys, increases absorption in the GI tract, and increases mobilization from the bones
• Calcitonin increases excretion in the kidneys and the storage from the bones

Hyperparathyroidism

• Primary Hyperparathyroidism entails excessive synthesis and secretion of parathyroid hormone (PTH) by abnormal chief cells of the parathyroid gland, or parathyroid adenoma
• It leads to persistent hypercalcemia, which means negative feedback control is lost, then secretion of PTH is not suppressed by high calcium levels
• Symptoms related to hypercalcemia mainly affect the kidneys, GI tract, and neuromuscular system
  • These symptoms can include Polydipsia and Polyuria, which decreases the ability of the kidneys to respond to antidiuretic hormone (ADH)
  • Calciuria can result in urolithiasis and secondary urinary tract infection (UTI)
  • Hyperparathyroidism depresses the excitability of the central and peripheral nervous systems, decreases GI smooth muscle excitability, and decreases cell membrane permeability of muscles
  • Cardiac arrhythmias (bradycardia) can be caused by hypercalcemia
• A diagnosis can be determined via urinalysis (crystalluria – calcium crystals) and serum biochemistry, which will indicate both total and ionized calcium levels are elevated
• Secondary hyperparathyroidism in horses (Nutritional secondary hyperparathyroidism (NSH), also known big-head disease), is caused by excessive mobilization of calcium from the skeleton under the influence of parathyroid hormone
• The condition occurs due to:
  • a dietary calcium deficiency
  • excess levels of phosphorus
  • an inverted calcium-to-phosphorus ratio in the total diet
  • high levels of oxalates in forages, which interfere with digestion and absorption of calcium
• Nutritional metabolic bone disease in reptiles and amphibians (NMBD) includes: Nutritional secondary hyperparathyroidism (NSHP)
• NSHP predisposing factors:
  • low dietary calcium and vitamin D3
  • inverted Ca:P ratio
  • lack of UV-B light exposure
  • inappropriate temperature gradient
• This can be caused by unappropriated diet and excessive production of parathyroid hormone (PTH) from the parathyroid gland in response to hypocalcemia
• Secondary hyperparathyroidism also occurs because of dietary and/or husbandry mismanagement, with the most implicated factors being prolonged deficiency of dietary calcium or vitamin D3, imbalance of the calcium-phosphorus ratio in the diet (usually an excess of phosphorus), and inadequate exposure to ultraviolet (UVB) radiation in diurnal animals

Hypoparathyroidism

• Hypoparathyroidism is an absolute or relative deficiency of parathyroid hormone (PTH)
• It can be idiopathic, which is most common, and caused by autoimmune destruction of the parathyroid or other causes, like trauma, agenesis, or surgical destruction of PT gland
• Inappropriately low levels of PTH classically result in hypocalcemia, decreased calcitriol, and hyperphosphatemia
• Symptoms may range from mild to severe, and are related to calcium deficiency, including muscle weakness, cramps, seizures, neuromuscular and neurologic signs, hypotension, decreased heart contractility, and skeletal deformities
• Diagnosis occurs via serum biochemistry: low total and ionized calcium, undetectable PTH concentrations, and hyperphosphatemia is common