Parathyroid Hormone and Calcitonin: Antagonistic Hormones
Maintenance of blood $Ca^{2+}$ levels largely depends on the balance of two peptide hormones.
Parathyroid hormone (PTH) is secreted by the parathyroid glands and raises blood calcium levels through three main pathways:
- In bone tissue: stimulates $Ca^{2+}$ mobilization, causing its release into the bloodstream.
- In the kidneys: enhances calcium ion reabsorption in the distal tubules.
- In the intestines: acts indirectly by activating the renal production of calcitriol, which in turn stimulates $Ca^{2+}$ absorption.
PTH secretion is regulated by negative feedback: as soon as blood calcium concentration rises, hormone production is suppressed.
Calcitonin is a 32-amino acid polypeptide with a single disulfide bond. It is synthesized by the parafollicular cells (C-cells) of the thyroid gland and C-cells of the parathyroid gland. Unlike PTH, it lowers calcium levels by inhibiting its release from bones and stimulating urinary excretion. Calcitonin secretion increases during hypercalcemia and decreases when calcium is deficient.
Biosynthesis and Mechanism of Action of Calcitriol
The active form of vitamin $D_3$ — calcitriol ($1,25(OH)_2D_3$) — is synthesized from cholesterol. A minor portion of precursors comes from diet, but the main pathway begins in the skin.
Conversion Stages (Skin-Liver-Kidney axis):
- Skin: 7-Dehydrocholesterol is non-enzymatically converted to cholecalciferol under ultraviolet light. This process cleaves the B ring of the steroid nucleus, forming a secosteroid structure (adding one hydroxyl group at position 3).
- Liver: Catalyzed by 25-hydroxylase, cholecalciferol is hydroxylated at carbon 25 to form calcidiol (two -OH groups: 3, 25).
- Kidneys: The rate-limiting step takes place. The enzyme $1\alpha$-hydroxylase adds a third hydroxyl group, forming calcitriol (three -OH groups: 1, 3, 25).
The renal enzyme is activated by parathyroid hormone and low $Ca^{2+}$ levels, and inhibited by calcitriol itself (feedback loop).
Calcitriol is transported in the blood bound to a carrier protein. Entering target cells (e.g., enterocytes), it binds to an intracellular receptor, interacts with chromatin, and alters translation rates. As a result, proteins that mediate calcium and phosphate absorption are synthesized.
Changes in Plasma Calcium Concentration
The excitability threshold of nerve and muscle cells, the function of calcium pumps, and the activity of numerous enzymes depend on calcium levels.
- Hypocalcemia (decreased $Ca^{2+}$ level) leads to increased neuromuscular excitability, clinically manifesting as hyperreflexia, tetany, and laryngospasm.
- Hypercalcemia (increased $Ca^{2+}$ level), conversely, causes decreased neuromuscular excitability. Severe neurological dysfunctions may occur, including psychoses, stupor, and coma.
Parathyroid Gland Pathologies
Hyperparathyroidism occurs due to excessive PTH secretion (e.g., from a tumor or glandular hyperplasia).
- Pathogenesis: excessive mobilization of calcium and phosphate from bone, enhanced renal calcium reabsorption, and increased renal phosphate excretion.
- Laboratory findings: hypercalcemia, hypophosphatemia (in blood), and hyperphosphaturia (in urine).
- Symptoms: muscle weakness, decreased excitability, myalgia, high risk of fractures (especially of the spine and hips), and kidney stone formation.
Hypoparathyroidism is parathyroid gland insufficiency. The main symptom is marked hypocalcemia. Patients suffer from tonic seizures (including diaphragmatic and respiratory muscle spasms), laryngospasm, and increased neuromuscular conductivity.
Rickets: Impaired Mineralization
Rickets is a pediatric disorder characterized by defective bone mineralization due to calcium deficiency.
Causes:
- Dietary vitamin $D_3$ deficiency or impaired intestinal absorption.
- Lack of sunlight exposure (reduced synthesis in the skin).
- Genetic defects of the $1\alpha$-hydroxylase enzyme or calcitriol receptors.
Due to impaired intestinal calcium absorption, blood calcium levels drop. This stimulates parathyroid hormone secretion (causing secondary hyperparathyroidism), which mobilizes calcium from the bones.
Clinical Manifestations:
- Tubular bone and joint deformities (bowlegs).
- Cranial bone defects.
- Pigeon chest (pectus carinatum).
- Potbelly abdomen.