Chapter Endocrinology
Introduction
Calcium is essential for numerous physiological processes, including neuromuscular transmission, blood coagulation, hormone secretion, and enzymatic function. Maintenance of normal serum calcium levels relies on the interplay of parathyroid hormone (PTH), vitamin D, and calcitonin, together with organ systems such as bone, kidneys, and the intestinal tract. Disruptions in these control mechanisms can result in hypercalcemia or hypocalcemia, each with distinct clinical implications. This lesson focuses on the pathophysiology, common causes, diagnostic approach, and basic management principles for calcium homeostasis disorders in small animals, aligned with the learning requirements for Membership in the Australian and New Zealand College of Veterinary Scientists (MANZCVS) in Small Animal Medicine.
Calcium Homeostasis
1.1. Physiological Components
• Parathyroid Hormone (PTH)
– Produced by parathyroid chief cells in response to hypocalcemia.
– Increases serum calcium by mobilizing bone resorption, enhancing renal calcium reabsorption, and stimulating active vitamin D production.
• Vitamin D (Calcitriol)
– Increases intestinal calcium (and phosphorus) absorption, promoting bone mineralization while also facilitating bone turnover.
– Formed from precursors in the skin or diet, requiring renal hydroxylation (1α-hydroxylase) for active form.
• Calcitonin
– Secreted by the thyroid parafollicular (C) cells in response to hypercalcemia.
– Decreases serum calcium by inhibiting bone resorption and promoting renal excretion.
1.2. Calcium Fractions in Blood
• Ionized Calcium (iCa)
– Biologically active form (~50% of total serum calcium).
– Most indicative of true calcium status.
• Protein-Bound Calcium
– Mainly bound to albumin (~40%).
• Complexed Calcium
– Bound to anions such as phosphate, lactate (~10%).
2. Hypercalcemia
2.1. Pathophysiology
• Excess PTH or PTHrP (PTH-related peptide) often drives persistent bone resorption and/or renal calcium reabsorption.
• Increased dietary or GI absorption of calcium can also contribute if coupled with inadequate renal excretion.
2.2. Causes of Hypercalcemia
• Malignancy-Associated
– Lymphoma, apocrine gland adenocarcinoma of the anal sac (AGASACA), multiple myeloma, osteosarcoma.
– Often due to PTHrP production or extensive bone lysis.
• Primary Hyperparathyroidism (PHPTH)
– Benign parathyroid adenoma is the most common cause in dogs.
– Excess PTH release leads to hypercalcemia with concurrent low or undetectable phosphate.
• Chronic Kidney Disease (CKD)
– Hyperphosphatemia and decreased calcitriol production may initially cause normal or reduced serum calcium, but advanced or long-standing disease can lead to hypercalcemia.
• Vitamin D Intoxication
– Oversupplementation, ingestion of vitamin D-containing rodenticides or plants (e.g., some rodenticides, calcipotriene creams).
– Results in excessive GI absorption and bone release of calcium.
• Granulomatous Diseases
– Activated macrophages can synthesize calcitriol, increasing calcium absorption.
• Hypoadrenocorticism (Addison’s Disease)
– Mechanism multifactorial; possible decreased renal clearance or increased bone resorption.
2.3. Clinical Signs of Hypercalcemia
• Polyuria, polydipsia (PU/PD)
• Anorexia, vomiting, constipation
• Weakness, lethargy, muscle tremors
• Cardiac arrhythmias (rare)
• Mineralization of soft tissues with chronic, severe hypercalcemia
3. Hypocalcemia
3.1. Pathophysiology
• Inadequate PTH production/action or vitamin D deficiency leads to decreased bone mobilization, reduced renal reabsorption, and/or poor intestinal absorption of calcium.
3.2. Causes of Hypocalcemia
• Hypoparathyroidism
– Immune-mediated destruction of parathyroid glands or surgical removal (accidental during thyroidectomy).
– Low PTH → persistent hypocalcemia, high phosphate.
• Eclampsia / Puerperal Tetany
– Lactating bitches or queens with high calcium demand; unable to mobilize sufficient calcium.
• Acute or Chronic Renal Failure
– Decreased calcitriol production, hyperphosphatemia, compromised PTH response.
• Pancreatitis
– Saponification of fat in the abdomen can sequester calcium; also possibly altered PTH response.
• Nutritional Imbalances
– Severe vitamin D deficiency, or diets with improper calcium:phosphorus ratios.
3.3. Clinical Signs of Hypocalcemia
• Neuromuscular Irritability
– Muscle tremors, twitching, tetany.
– Facial rubbing, focal or generalized seizures.
• Behavioral Changes
– Restlessness, anxiety, aggression in some cases.
• Cardiovascular Manifestations
– Prolonged QT interval on ECG.
4. Diagnostic Approach
4.1. Laboratory Tests
• Total Serum Calcium
– A quick screening measure, but interpret in context of albumin levels.
– Corrected calcium formula can adjust for hypoalbuminemia but less accurate than ionized calcium.
• Ionized Calcium (iCa)
– Gold standard to confirm true hypercalcemia or hypocalcemia.
– Analyze promptly or in specific conditions to avoid pH changes affecting iCa.
• Serum Phosphorus
– Often inversely related to calcium.
– Elevated in hypoparathyroidism or renal disease.
• Serum PTH
– In hypercalcemia, an inappropriately normal or high PTH indicates primary hyperparathyroidism.
– Undetectable PTH suggests malignancy-driven or other non-parathyroid cause.
• PTHrP (PTH-related peptide)
– High levels support malignancy-driven hypercalcemia (especially lymphoma, AGASACA).
• Vitamin D Metabolites (25(OH)D, 1,25(OH)2D)
– Evaluate for toxicity (excess vitamin D) or deficiency.
• Additional Diagnostics
– Imaging: Radiographs or ultrasound for masses (e.g., parathyroid adenoma, neoplasia).
– Renal function tests, fractional excretion of calcium, etc.
4.2. Differential Diagnosis
• Hypercalcemia of Malignancy vs. Primary Hyperparathyroidism
– Evaluate PTH, PTHrP, imaging (lymph nodes, anal sacs, parathyroid glands).
• Hypoparathyroidism vs. Secondary Hypocalcemia (Renal, Nutritional)
– Check PTH levels, phosphate levels, renal ultrasound, dietary history.
5. Management Principles
5.1. Hypercalcemia
(1) Acute Stabilization
• IV Fluid Therapy
– Saline diuresis to promote calciuresis (increased renal calcium excretion).
– Avoid lactated Ringer’s if severely hypercalcemic, as lactate metabolism may release HCO3– and potentially influence calcium binding.
• Diuretics (e.g., Furosemide)
– Only after adequate volume expansion.
– Helps increase calcium excretion.
• Glucocorticoids
– Indicated if suspect lymphoma, Addison’s disease, or vitamin D toxicosis, as steroids decrease bone/GI absorption of calcium.
– Avoid pre-diagnostic therapy in some suspected neoplasms if possible (can mask definitive diagnosis).
(2) Definitive or Long-Term Management
• Address Underlying Cause
– Surgical removal of parathyroid adenoma, anal sac adenocarcinoma.
– Chemotherapy or radiation for lymphoma.
– Treat hypervitaminosis D with steroids, supportive care.
• Bisphosphonates (e.g., Pamidronate, Alendronate)
– Inhibit osteoclast-mediated bone resorption; used in refractory or palliative settings.
5.2. Hypocalcemia
(1) Acute Therapy
• IV Calcium Gluconate
– Administer slowly while monitoring ECG for bradycardia or arrhythmias.
– Alleviates neuromuscular symptoms promptly.
• Magnesium Supplementation
– Evaluate and correct if concurrent hypomagnesemia is present (important for PTH secretion/action).
(2) Chronic Management
• Oral Calcium and Vitamin D Supplementation
– Calcium carbonate or citrate plus active vitamin D analogs (calcitriol) or ergocalciferol.
• Hypoparathyroidism
– Lifelong supplementation with calcitriol ± calcium.
– Monitor serum calcium to prevent hypercalcemia.
6. Monitoring and Prognosis
6.1. Follow-Up Tests
• Serial Ionized Calcium Measurements
– Monitor therapy response in hypercalcemia or hypocalcemia.
• PTH, PTHrP Re-Evaluation
– Assess resolution or progression of underlying disease.
• Renal and Cardiovascular Parameters
– Check for nephrocalcinosis in hypercalcemia or arrhythmias in hypocalcemia.
6.2. Prognosis
• Depends on underlying etiology—malignancies have variable outlooks; primary hyperparathyroidism often good prognosis if adenoma is resected.
• Hypocalcemia from hypoparathyroidism can be well-controlled long-term with appropriate therapy.
Conclusion
Disorders of calcium homeostasis—whether hypercalcemia or hypocalcemia—can severely impact canine and feline patients. Understanding physiological mechanisms, recognizing the range of potential causes, and applying targeted diagnostic tests (ionized calcium, PTH, PTHrP) are essential steps in determining etiology. Effective management hinges on stabilizing acute derangements—through IV fluids, careful administration of calcium, or specific treatments (e.g., bisphosphonates)—and addressing the root cause (e.g., neoplasia, hypoparathyroidism). Through vigilant monitoring and appropriate follow-up testing, veterinarians can optimize clinical outcomes for patients with calcium disorders, a key skill for those working toward MANZCVS Small Animal Medicine certification.
Suggested References
Kittleson, M. D., & Kienle, R. D. (1998). Small Animal Cardiovascular Medicine. Mosby. (For cardiac effects of calcium disorders)
Peterson, M. E., & Moroff, S. D. (1984). Primary hyperparathyroidism in dogs. Journal of the American Veterinary Medical Association, 185(2), 200–207.
Chew, D. J., et al. (2002). Disorders of calcium: Hypercalcemia and hypocalcemia. In Consultations in Feline Internal Medicine, Vol. 5. Elsevier.
Bruyette, D. S. (2015). Disturbances of calcium: Hypercalcemia and hypocalcemia. In Ettinger, S. J., & Feldman, E. C. (Eds.), Textbook of Veterinary Internal Medicine (8th ed.). Elsevier.
Peterson, M. E. (2012). Primary hyperparathyroidism in cats: 20 cases. Journal of Veterinary Internal Medicine, 26(2), 294–303.
Haberer, J. L., & Forrester, S. D. (2017). Hypoparathyroidism. Veterinary Clinics of North America: Small Animal Practice, 47(2), 303–315.