Hypercalcemia in Dogs – A Clinical Approach

Philip R Judge BVSc MVS PG Cert Vet Stud MACVS (vet. Emergency and Critical Care, Medicine of Dogs)

Introduction

Hypercalcaemia is a serious clinical finding that has a diverse aetiology, requiring both a thorough patient evaluation, and prompt emergency management to achieve optimal outcome for the patient. This short review discusses the physiology of calcium homeostasis, aetiology, clinical signs and emergency management of the patient with hypercalcaemia.

Understanding Calcium Regulation

Calcium is a critical electrolyte involved in neuromuscular transmission, enzyme function, blood clotting, vascular tone, and skeletal stability. Because of its role in cell function, even moderate disruptions in calcium balance can lead to significant illness. Calcium levels are maintained through a complex interplay of three main hormones: calcitriol, parathyroid hormone (PTH), and calcitonin. When evaluating a patient, it is important to note that ionized calcium is the biologically active form and provides a more accurate assessment than total calcium, which can overestimate or underestimate true calcium status.

Key Points:

• Calcium is acquired through dietary intake 
• Calcitriol (activated vitamin D) increases intestinal calcium absorption and supports reabsorption in the kidneys and bones.
• Parathyroid hormone (PTH) raises serum calcium by inducing osteoclastic bone resorption, increasing renal reabsorption, and stimulating calcitriol production.
• Calcitonin, released by the thyroid gland, lowers calcium by inhibiting osteoclast activity when levels become excessive.
• Ionised calcium measurement is the preferred method for both initial diagnosis and ongoing monitoring of hypercalcemia.

Physiology and Clinical Signs

Increased serum ionised calcium concentrations alter cellular function by altering cell membrane permeability, and cell membrane calcium pump activity. Any alteration in cell membrane permeability, or alteration/inactivation of the cell membrane calcium pump causes

• Deranged cell function
• Decreased cellular energy production
• Cell membrane disruption

Body systems that are most affected are the central nervous system, heart, lungs, gastrointestinal tract and kidneys. Clinical signs are dependent on the rapidity of development of hypercalcaemia, the magnitude of hypercalcaemia, and the duration of hypercalcaemia

The clinical signs of hypercalcaemia reflect its widespread physiological impact, affecting the gastrointestinal, renal, neuromuscular, and cardiovascular systems. Severity of clinical presentation varies widely, from asymptomatic presentations, where hypercalcaemia is discovered incidentally on routine bloodwork to life-threatening emergencies with seizures or cardiac arrhythmias. 

Clinical signs are most severe when hypercalcaemia develops quickly, as in hypervitaminosis D, and iatrogenic excess intravenous administration.

Mineralisation of soft tissues occurs when the product of calcium and phosphorus is greater than 4 mmol/L (50 mg/dl); and can occur in any tissue. Clinical effects are often initially noted in reduced cardiac function (arrhythmias) and kidney function (AKI).

Clinical signs associated with hypercalcaemia include:

• Kidney symptoms
  • Polyuria and decreased urinary concentrating ability – early clinical signs, result from decreased tubular reabsorption of sodium, and impaired action of ADH on the collecting duct tubular cells mediated by calcium sensing receptors on the renal epithelial cells in response to hypercalcaemia
  • Acute kidney injury: mineralisation of the tubular basement membranes, tubular degeneration, and interstitial fibrosis contribute to renal structural changes. These changes are potentially reversible, but may become permanent if hypercalcaemia persists
  • Azotemia is common, and results from pre-renal (dehydration – due to polyuria, vomiting, diarrhoea) and renal causes. A compensatory polydypsia may diminish as hypercalcaemia persists, leading to dehydration.
• Gastrointestinal symptoms
  • Occur due to decreased excitability of smooth muscle
  • Gastrointestinal symptoms include reduced appetite, vomiting and constipation 
• CNS symptoms
  • Occur due to brain calcification, and altered trans-membrane calcium concentrations, leading to hypo-excitability of neurons
  • Symptoms include depression, lethargy, coma, and occasionally, seizures
• Decreased excitability of skeletal muscle causes weakness
• Cardiac symptoms
  • Increased PR interval, decreased QT interval
  • Ventricular arrhythmias – cardiac changes develop as a result of rapid mineralisation of heart muscle, and the effect of elevated extracellular calcium concentrations

Key Points:

• Common signs include vomiting, diarrhoea, polyuria, polydipsia, anorexia, muscle weakness, and tremors.
• Severe hypercalcaemia can lead to seizures and cardiac arrhythmias requiring emergency intervention.
• Chronic hypercalcaemia may contribute to renal failure, while acute cases can cause prerenal azotemia.
• Without addressing the underlying cause, hypercalcaemia will persist despite symptomatic treatment.
• Comprehensive diagnostics and targeted therapy are essential for achieving lasting clinical resolution.

Common Causes: The HARDIONS Mnemonic

Hypercalcaemia in dogs can arise from a variety of underlying conditions, ranging from endocrine disorders to toxin exposure. The mnemonic HARDIONS provides a practical framework for remembering the most frequently encountered causes. Among these, neoplasia is by far the most common, accounting for approximately 60% of cases. Other causes, such as primary hyperparathyroidism and hypoadrenocorticism, are less frequent but remain important differentials that require specific diagnostic testing.

Key Points:

• H – Hyperparathyroidism (primary) and hypercalcemia of malignancy (HM).
• A – Addison’s disease (hypoadrenocorticism), seen in about one-third of affected dogs.
• R – Renal disease or failure, often secondary to another primary condition.
• D – Vitamin D toxicity, including cholecalciferol rodenticides and supplement overdoses.
• I – Idiopathic hypercalcemia, which is common in cats but very rare in dogs.
• O – Osteolytic conditions such as osteomyelitis or bone tumours releasing calcium directly.
• N – Neoplasia, with lymphoma and apocrine gland anal sac adenocarcinoma being the most common malignancies. Other malignant tumours causing hypercalcaemia include mammary carcinoma, renal tumours, multiple myeloma, thymoma and primary bone tumours
• S – Spurious causes, including lab errors, lipaemic samples, or haemoconcentration.

Hypercalcaemia of Malignancy

Malignancy-associated hypercalcaemia is the leading pathologic cause in dogs, most frequently linked to T-cell lymphoma and apocrine gland anal sac adenocarcinoma, though it can also occur with multiple myeloma, thymoma, melanoma, mammary tumours, and pancreatic, lung, testicular, and nasal cavity tumours. 

Tumour cells of many tumours, including lymphoma, apocrine gland adenocarcinoma, multiple myeloma, thymoma and numerous carcinomas (thyroid, bronchogenic, pancreatic, skin, mammary and squamous cell) secrete parathyroid hormone-related peptide (PTHrP), which mimics the action of PTH and results in excessive bone resorption and renal calcium retention. 

In other cases, direct osteolysis from bone tumours can also contribute by releasing stored calcium directly into the circulation.

Key Points:

• PTHrP acts similarly to PTH by stimulating osteoclast activity and increasing renal tubule calcium reabsorption.
• Other cytokines and growth factors released by tumours, including TNF, IL-1 and PG E₂ can also cause bone resorption 
• Direct bone invasion or metastasis can cause hypercalcaemia through local osteolysis.
• The HM (hypercalcaemia of malignancy) panel (testing PTH, ionised calcium, and PTHrP) is essential for differentiating malignancy from primary hyperparathyroidism.

Diagnostic Approach

A thorough and systematic diagnostic workup is critical for identifying the underlying cause of hypercalcaemia and guiding appropriate treatment. Baseline testing should include a complete blood count, comprehensive biochemical profile, and urinalysis, with special attention to phosphorus levels and renal parameters. Imaging plays a key role in detecting neoplasia, and additional tests such as the HM panel help distinguish between malignant and parathyroid-mediated causes. In cases where primary hyperparathyroidism is suspected, a thyroid and parathyroid ultrasound can identify nodules that are often benign but that require intervention.

Key Points:

• Baseline lab work helps identify concurrent abnormalities such as azotemia or hyperphosphataemia.
• Thoracic radiography and abdominal ultrasonography are recommended to evaluate for masses or metastatic disease.
• Ultrasound-guided fine-needle aspiration or biopsy should be pursued if a suspicious lesion is identified.
• The HM panel provides definitive differentiation: elevated PTH with hypercalcaemia indicates hyperparathyroidism, while low PTH with positive PTHrP suggests malignancy.
• Parathyroid ultrasound can confirm nodular disease in suspected primary hyperparathyroidism cases.

Treatment Strategies

The cornerstone of hypercalcaemia management is addressing the underlying disease process, whether through surgical removal of a tumour, chemotherapy, or targeted treatment of an endocrine disorder. However, supportive care is often necessary to stabilise patients with severe clinical signs or significantly elevated calcium levels. The choice of therapy depends on the severity of hypercalcaemia, the patient’s clinical status, and the suspected or confirmed aetiology. Emergent intervention is indicated for total calcium levels exceeding 4.5 mmol/L or ionized calcium above 1.6 mmol/L with significant symptoms.

Key Points:

• Surgical excision of neoplasms (e.g., anal sac adenocarcinoma) is the gold standard for malignancy-associated hypercalcemia.
• For primary hyperparathyroidism, parathyroidectomy is preferred, with ethanol ablation as an alternative for non-surgical candidates.
• First-line supportive care includes 0.9% NaCl fluid diuresis (100–125 mL/kg/day) and loop diuretics like furosemide (2–4 mg/kg q 8–12h).
• Glucocorticoids are effective for neoplasia-related hypercalcemia but should avoided if possible before a definitive diagnosis is obtained, as they can interfere with cytology and PTHrP testing.

Additional Treatment Options

When first-line therapies are insufficient or contraindicated, several additional agents can be employed to lower calcium levels. Bisphosphonates have become a mainstay for longer-term control, particularly in cases involving bone neoplasia. Other drugs, such as mithramycin and calcitonin, offer rapid but short-lived effects and are best reserved for acute, severe presentations. Calcimimetics represent a newer class of medications that lower PTH, that may be useful in specific scenarios like primary hyperparathyroidism or renal failure.

Key Points:

• Bisphosphonates (e.g., zoledronate 0.1–0.2 mg/kg IV over 15 minutes) inhibit osteoclast activity, with effects starting in 24–48 hours; they require caution in renal disease.
• Mithramycin is a cytotoxic antibiotic that reduces activity of osteoclasts, reducing bone resorption in response to PTH. It provides rapid calcium reduction but carries risks of hepatotoxicity, bone marrow suppression, and renal toxicity.
• Calcitonin reduces bone resorption, and increases calcium loss via renal excretion. It acts quickly but loses efficacy within 12–24 hours due to resistance. 
• Calcimimetics bind to, and activate calcium-sensing receptors in the parathyroid glands, reducing PTH secretion, and subsequent activity of PTH. They are useful in management of hyperparathyroidism and kidney failure.

Prognosis

Ultimately, the prognosis depends on the underlying cause and the ability to treat it effectively. While supportive care can stabilise a patient, long-term resolution requires definitive management of the primary disease process.

References:

1. Quesnell B. Hypercalcemia in dogs: emergent care, diagnostics, and treatments. TVN. 2023;(2023-03):1-8.
2. Coady M, Fletcher DJ, Goggs R. Severity of ionized hypercalcemia and hypocalcaemia is associated with aetiology in dogs and cats. Frontiers in Veterinary Science. 2019 Aug 22;6:468382.
3. Daniels E, Sakakeeny C. Hypercalcemia: pathophysiology, clinical signs, and emergent treatment. Journal of the American Animal Hospital Association. 2015 Sep 1;51(5):291-9.
4. Groman AR. Acute management of calcium disorders. Topics in companion animal medicine. 2012 Nov 1;27(4):167-71.
5. DiBartola SP. Fluid, electrolyte, and acid-base disorders in small animal practice. WB Saunders; 2011 Jun 22.
6. de Morais HA, DiBartola SP. Advances in Fluid, Electrolyte, and Acid-base Disorders, An Issue of Veterinary Clinics of North America: Small Animal Practice. Elsevier Health Sciences; 2017 Feb 8.