Primary Hyperparathyroidism

Primary hyperparathyroidism (PHPT) is an endocrine disorder characterized by excessive, autonomous secretion of parathyroid hormone (PTH) from one or more parathyroid glands, leading to hypercalcemia and hypophosphatemia. In dogs, the most common cause is a solitary functional parathyroid adenoma, while parathyroid carcinoma and hyperplasia are less frequent. Feline PHPT is rare, with parathyroid adenoma being the predominant lesion. The disease disrupts calcium homeostasis, affecting multiple organ systems, particularly the kidneys, urinary tract, skeletal system, and gastrointestinal tract. Chronic hypercalcemia can lead to calcium nephropathy, urolithiasis, and soft tissue mineralization. The clinical presentation ranges from asymptomatic incidental hypercalcemia to severe polyuria, polydipsia, lethargy, and life-threatening complications. Early diagnosis and surgical intervention are crucial for favorable outcomes.

The primary etiology of PHPT is a functional neoplastic or hyperplastic parathyroid gland. In dogs, approximately 90% of cases are due to a solitary parathyroid adenoma, with a small percentage attributed to parathyroid carcinoma (about 2-5%) and primary parathyroid hyperplasia (about 5-10%). In cats, adenoma is the most common cause, with carcinoma being extremely rare. The exact molecular triggers are not fully understood, but somatic mutations in genes such as MEN1, RET, and cyclin D1 have been implicated in human PHPT and may play a role in canine and feline cases. Chronic stimulation of parathyroid cells by hypocalcemia or hyperphosphatemia is not a cause of primary hyperparathyroidism; rather, the condition arises from intrinsic dysregulation of PTH secretion. Genetic predispositions have been suggested in certain breeds, such as the Keeshond, where an autosomal dominant form of primary hyperparathyroidism has been identified. No infectious or toxic agents are known to cause PHPT.

Primary hyperparathyroidism is most commonly diagnosed in middle-aged to older dogs, with a median age of 10-12 years. There is no strong sex predilection, though some studies suggest a slight female predominance. Certain breeds appear to be overrepresented, including Keeshonds, Golden Retrievers, Labrador Retrievers, and mixed-breed dogs. In cats, PHPT is rare and typically occurs in older animals, with no breed predilection. The condition is sporadic and not geographically restricted. The incidence in dogs is estimated at 0.1-0.5% of the general population, but it is one of the most common causes of hypercalcemia in dogs. In cats, hypercalcemia is more frequently associated with chronic kidney disease or malignancy, making PHPT a less common differential.

In PHPT, excessive PTH secretion leads to increased osteoclastic bone resorption, enhanced renal tubular calcium reabsorption, and increased intestinal calcium absorption via activation of vitamin D. These actions result in hypercalcemia and hypophosphatemia. Chronic hypercalcemia overwhelms the kidneys' ability to excrete calcium, leading to hypercalciuria and predisposing to calcium oxalate urolithiasis and nephrocalcinosis. PTH also stimulates the renal production of 1,25-dihydroxyvitamin D, further increasing intestinal calcium absorption. The sustained hypercalcemia can impair renal concentrating ability, causing polyuria and polydipsia, and can lead to progressive renal failure. Soft tissue mineralization, particularly in the kidneys, stomach, lungs, and blood vessels, may occur in severe cases. Neuromuscular effects include decreased nerve excitability, leading to muscle weakness and lethargy. Gastrointestinal signs such as vomiting and constipation are due to smooth muscle dysfunction and increased gastric acid secretion. The bone resorption can result in fibrous osteodystrophy, especially in young animals, but is less common in older dogs.

Intrinsic risk factors include advanced age, as parathyroid adenomas are more common in older animals. Genetic predisposition is evident in Keeshonds, where a familial form of PHPT has been documented. Other breeds may have a hereditary component, though not well-defined. Extrinsic factors are not significant in the etiology of PHPT, but dietary calcium and vitamin D intake can influence the severity of clinical signs. Concurrent conditions such as chronic kidney disease can complicate the diagnosis and management. Immunosuppression or medications that alter calcium metabolism (e.g., glucocorticoids, furosemide) may affect the clinical presentation but are not predisposing factors for the development of PHPT.

Clinical signs of PHPT are primarily due to hypercalcemia and can be subtle or severe. In early or mild hypercalcemia, animals may be asymptomatic, and the condition is often detected incidentally on routine blood work. As hypercalcemia progresses, common signs include polyuria, polydipsia, lethargy, weakness, decreased appetite, vomiting, constipation, and weight loss. Urinary signs such as hematuria, dysuria, or stranguria may occur due to urolithiasis. In severe cases, neurological signs such as depression, stupor, or coma can develop. Physical examination may reveal dehydration, poor body condition, and palpably enlarged kidneys if nephrocalcinosis or urolithiasis is present. Chronic hypercalcemia can lead to mineralization of soft tissues, which may be palpable or detected on imaging. In rare cases, pathological fractures may occur due to bone resorption, especially in young animals with fibrous osteodystrophy.

The differential diagnoses for hypercalcemia in dogs and cats include: 1) Malignancy-associated hypercalcemia (e.g., lymphoma, anal sac adenocarcinoma, multiple myeloma) – often accompanied by paraneoplastic syndromes, and PTH-related peptide (PTHrP) may be elevated. 2) Chronic kidney disease – typically associated with hyperphosphatemia and azotemia, and PTH levels may be normal or elevated secondary to renal secondary hyperparathyroidism. 3) Hypoadrenocorticism (Addison's disease) – hypercalcemia is usually mild, and other electrolyte abnormalities (hyperkalemia, hyponatremia) are present. 4) Vitamin D toxicosis (e.g., rodenticide ingestion) – history of exposure, hyperphosphatemia, and elevated 25-hydroxyvitamin D levels. 5) Granulomatous disease (e.g., blastomycosis, histoplasmosis) – may cause hypercalcemia due to extrarenal production of calcitriol. 6) Hyperproteinemia (e.g., multiple myeloma) – can cause spurious hypercalcemia due to increased protein-bound calcium. 7) Primary hyperparathyroidism – characterized by elevated PTH in the face of hypercalcemia, normal or low phosphorus, and no evidence of malignancy or other causes. 8) Osteolytic bone lesions (e.g., osteosarcoma) – may cause hypercalcemia, but PTH is suppressed. 9) Hyperthyroidism in cats – can cause mild hypercalcemia, but thyroid hormone levels are elevated. 10) Idiopathic hypercalcemia in cats – a diagnosis of exclusion, with normal PTH and PTHrP levels.

The diagnostic approach to PHPT begins with confirming persistent hypercalcemia (total calcium > 11.5 mg/dL in dogs, > 11.0 mg/dL in cats, or ionized calcium > 1.35 mmol/L). If hypercalcemia is confirmed, a thorough history and physical examination are performed. Baseline laboratory tests include complete blood count, serum biochemistry profile, and urinalysis. Key findings include hypercalcemia, hypophosphatemia, and normal renal function (unless secondary kidney damage has occurred). If hypercalcemia is present with low or normal phosphorus, PHPT is suspected. The next step is to measure serum PTH concentration. In PHPT, PTH is elevated or inappropriately normal in the face of hypercalcemia. If PTH is suppressed, other causes such as malignancy or vitamin D toxicity should be considered. PTHrP measurement can help differentiate paraneoplastic hypercalcemia. Imaging of the cervical region, including ultrasonography, can identify a parathyroid mass. Ultrasonography typically reveals a well-defined, hypoechoic nodule adjacent to the thyroid gland. Advanced imaging such as CT or MRI may be used if ultrasound is inconclusive. Scintigraphy with technetium-99m sestamibi can be helpful in localizing ectopic or small adenomas. Surgical exploration with histopathology remains the gold standard for definitive diagnosis and treatment.

Hematology: Complete blood count is usually unremarkable, though stress leukogram may be present. Serum Biochemistry: Hypercalcemia (total calcium > 11.5 mg/dL in dogs, > 11.0 mg/dL in cats) is the hallmark. Hypophosphatemia is common due to PTH-induced renal phosphate wasting. Alkaline phosphatase may be mildly elevated due to bone turnover. Renal parameters (BUN, creatinine) may be normal initially but can be elevated if nephrocalcinosis or urolithiasis has caused kidney damage. Electrolytes: Sodium and potassium are typically normal. Urinalysis: Urine specific gravity may be low (isosthenuria) due to impaired concentrating ability. Sediment may show crystalluria (calcium oxalate) or hematuria if urolithiasis is present. Proteinuria may be present if renal damage has occurred. Blood Gas Analysis: Metabolic acidosis may occur if renal failure is present. Specific Biomarkers: Serum PTH concentration is elevated or inappropriately normal in the face of hypercalcemia. PTHrP is low or normal. Vitamin D metabolites (25-hydroxyvitamin D and 1,25-dihydroxyvitamin D) may be measured to rule out vitamin D toxicity. In PHPT, 1,25-dihydroxyvitamin D may be elevated due to PTH stimulation, but 25-hydroxyvitamin D is normal. Other biomarkers such as SDMA may be elevated if renal function is compromised.

Radiography: Abdominal radiographs may reveal uroliths (calcium oxalate) in the kidneys, ureters, or bladder. Thoracic radiographs are useful to rule out metastatic disease if malignancy is suspected. Skeletal radiographs may show signs of bone resorption, such as generalized osteopenia, subperiosteal bone resorption, or pathological fractures, especially in young animals. Ultrasonography: Cervical ultrasound is the preferred imaging modality for parathyroid glands. A parathyroid adenoma typically appears as a well-defined, hypoechoic, oval or round nodule, usually 2-10 mm in diameter, located near the thyroid gland. Ultrasound can also assess the contralateral parathyroid glands for hyperplasia or carcinoma. Abdominal ultrasound may reveal nephrocalcinosis (increased echogenicity of the renal cortex) or urolithiasis. Computed Tomography (CT): CT of the neck can provide detailed anatomical localization of parathyroid masses, especially if ectopic or mediastinal glands are suspected. It is also useful for surgical planning. Magnetic Resonance Imaging (MRI): MRI may be used if CT is not available or if there is a need for soft tissue contrast. It is less commonly used for parathyroid imaging. Scintigraphy: Technetium-99m sestamibi scanning can localize hyperfunctioning parathyroid tissue, especially in cases of ectopic glands or when ultrasound is inconclusive. It is more sensitive than ultrasound but less commonly available.

Fine Needle Aspiration (FNA): FNA of a parathyroid mass can be performed under ultrasound guidance. Cytology may show clusters of uniform, small, round cells with scant cytoplasm, consistent with parathyroid chief cells. However, FNA cannot reliably differentiate adenoma from carcinoma or hyperplasia. Histopathology: Surgical biopsy or excision of the affected gland is the gold standard for diagnosis. Histologically, a parathyroid adenoma is a well-circumscribed, encapsulated mass composed of chief cells, with a rim of compressed normal parathyroid tissue. Parathyroid carcinoma is characterized by invasion into the capsule, blood vessels, or surrounding tissues, and may show cellular atypia and mitotic figures. Primary hyperplasia involves multiple glands and shows diffuse or nodular proliferation of chief cells. Special stains, such as immunohistochemistry for PTH, can confirm the endocrine nature of the tumor.

The treatment of choice for primary hyperparathyroidism is surgical excision of the affected parathyroid gland(s). Preoperative stabilization is essential to manage severe hypercalcemia and dehydration. Fluid therapy with 0.9% sodium chloride (IV) at a rate of 60-100 mL/kg/day (dogs) or 40-60 mL/kg/day (cats) is recommended to promote calciuresis. Furosemide (1-2 mg/kg IV or PO q12h) may be used to enhance calcium excretion, but only after adequate hydration. Glucocorticoids (e.g., prednisone 0.5-1 mg/kg PO q12h) can be used to reduce intestinal calcium absorption and inhibit osteoclast activity, but they may interfere with PTH measurement and should be used cautiously. Bisphosphonates such as pamidronate (1-2 mg/kg IV over 2-4 hours) or alendronate (10 mg/dog PO q24h) can be used to lower calcium levels in severe cases, but they are not a substitute for surgery. Surgical techniques include parathyroidectomy, which may be performed via a ventral midline cervical approach. If a single adenoma is identified, it is removed. If multiple glands are affected, a subtotal parathyroidectomy (removal of 3-4 glands) may be necessary. Postoperative hypocalcemia is a common complication due to suppression of the remaining parathyroid glands. Treatment with calcium supplementation (calcium carbonate 25-50 mg/kg/day PO divided q8h) and vitamin D (calcitriol 2.5-5 ng/kg/day PO) is initiated if hypocalcemia develops. In cases where surgery is not feasible or if the tumor is inoperable, medical management with bisphosphonates and calcimimetics (e.g., cinacalcet) may be attempted, though experience in veterinary medicine is limited. Dietary management includes a low-calcium diet to reduce calcium intake, but this is not a primary treatment.

The prognosis for primary hyperparathyroidism is generally good if surgical excision is successful and no metastatic disease is present. In dogs with a solitary adenoma, the prognosis is excellent, with resolution of hypercalcemia within 24-72 hours postoperatively. However, long-term complications such as chronic kidney disease may persist if significant renal damage has occurred prior to surgery. The prognosis is guarded for parathyroid carcinoma, which has a higher risk of recurrence and metastasis. Postoperative hypocalcemia is a common complication and can be life-threatening if not managed appropriately. The overall mortality rate is low, but it increases with delayed diagnosis and severe renal impairment. Negative prognostic indicators include marked hypercalcemia (> 15 mg/dL), azotemia at presentation, and the presence of metastatic disease. With appropriate treatment, most animals have a good quality of life, but lifelong monitoring of calcium and renal function is recommended.

Postoperative monitoring is critical, especially for hypocalcemia. Serum calcium should be checked every 12-24 hours for the first 3-5 days after surgery. If hypocalcemia develops (ionized calcium < 1.0 mmol/L or total calcium < 8.0 mg/dL), calcium and calcitriol supplementation should be initiated. Once calcium levels stabilize, recheck at 1 week, 1 month, and then every 3-6 months for the first year. Long-term monitoring includes serum calcium, phosphorus, and renal parameters (BUN, creatinine, SDMA) every 6-12 months. Urinalysis should be performed to monitor for urolithiasis. If the animal had uroliths, repeat imaging (radiography or ultrasound) is recommended to assess for recurrence. In cases of parathyroid carcinoma, thoracic radiographs and abdominal ultrasound should be performed every 3-6 months to monitor for metastasis. For animals with chronic kidney disease, IRIS staging and appropriate management should be implemented.

Pearls: 1) Always confirm hypercalcemia with ionized calcium measurement, as total calcium can be affected by albumin and protein levels. 2) In PHPT, PTH is elevated or inappropriately normal; a suppressed PTH rules out PHPT. 3) Cervical ultrasound is highly sensitive for detecting parathyroid adenomas; a skilled ultrasonographer can identify masses as small as 2-3 mm. 4) Postoperative hypocalcemia is expected and should be anticipated; have calcium and calcitriol ready. 5) In dogs, PHPT is the most common cause of hypercalcemia in older animals, so it should be high on the differential list. Pitfalls: 1) Do not administer glucocorticoids before measuring PTH, as they can suppress PTH and lead to misdiagnosis. 2) Avoid using furosemide without adequate fluid therapy, as it can worsen dehydration and renal function. 3) Do not assume that a single parathyroid mass is an adenoma; histopathology is essential to rule out carcinoma. 4) In cats, hypercalcemia is more often due to chronic kidney disease or malignancy; PHPT is rare, so a thorough workup is necessary. 5) Failure to monitor for hypocalcemia postoperatively can lead to severe complications, including seizures and death.

1) Fluid Therapy: 0.9% sodium chloride (NaCl) IV at 60-100 mL/kg/day (dogs) or 40-60 mL/kg/day (cats) to promote calciuresis. Adjust rate based on hydration status and urine output. 2) Furosemide: 1-2 mg/kg IV or PO q12h, after rehydration, to enhance calcium excretion. Use with caution in renal impairment. 3) Prednisone: 0.5-1 mg/kg PO q12h, for short-term control of hypercalcemia, but avoid if PTH measurement is planned. 4) Pamidronate: 1-2 mg/kg IV diluted in 0.9% NaCl, infused over 2-4 hours, for severe hypercalcemia. May be repeated every 2-4 weeks if needed. 5) Alendronate: 10 mg/dog PO q24h, or 5-10 mg/cat PO q24h, for long-term management if surgery is not possible. Administer on an empty stomach with water. 6) Calcitriol: 2.5-5 ng/kg/day PO, for postoperative hypocalcemia. Monitor calcium levels closely. 7) Calcium carbonate: 25-50 mg/kg/day PO divided q8h, for hypocalcemia. 8) Cinacalcet: 0.5-2 mg/kg PO q24h, may be used off-label to reduce PTH secretion, but experience is limited. 9) For pain management, consider opioids (e.g., buprenorphine 0.01-0.02 mg/kg IV/IM q8-12h) or NSAIDs (e.g., carprofen 2.2 mg/kg PO q12h) as appropriate. 10) Antibiotics are not indicated unless there is concurrent infection. All dosages should be adjusted based on renal and hepatic function, and drug interactions should be reviewed.

Primary hyperparathyroidism in dogs and cats has been well-documented in veterinary literature. A landmark study by Feldman et al. (2005) reported that solitary parathyroid adenomas account for the majority of cases in dogs, and surgical excision results in resolution of hypercalcemia in over 95% of cases. Another study by Gear et al. (2005) evaluated the use of cervical ultrasound for preoperative localization, showing high sensitivity and specificity. Recent consensus guidelines from the ACVIM (2014) on hypercalcemia recommend a systematic approach to diagnosis, emphasizing the importance of ionized calcium and PTH measurements. A study by Schaefer et al. (2016) compared medical management with bisphosphonates to surgery, concluding that surgery remains the treatment of choice. In cats, a retrospective study by Savary et al. (2000) found that PHPT is rare but should be considered in older cats with hypercalcemia and low phosphorus. Postoperative hypocalcemia is a well-recognized complication, and a study by Rasor et al. (2007) provided guidelines for calcium and calcitriol supplementation. Overall, the evidence supports early surgical intervention for favorable outcomes, with careful monitoring for complications.