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Treatment of primary hyperparathyroidism in a Miniature Horse using chemical ablation of abnormal parathyroid tissue localized by 3‐phase computed tomography

Abstract A 15‐year‐old Miniature Horse mare with persistently increased plasma calcium (total and ionized) and serum parathyroid hormone concentrations was presented for suspected primary hyperparathyroidism. Ultrasonography of the thyroid region identified an enlarged heterogeneous mass axial to the right thyroid lobe suggestive of an enlarged parathyroid gland, which was further confirmed using sestamibi nuclear scintigraphy and 3‐phase computed tomography. Percutaneous ultrasound‐guided ethanol ablation of the mass, a method not previously described in the horse, was performed under general anesthesia resulting in rapid normalization of plasma ionized calcium and serum parathyroid hormone concentrations. Ablation of abnormal parathyroid gland tissue may be a suitable alternative to surgical resection in certain cases of primary hyperparathyroidism in the horse.


| CASE HISTORY
The mare had a history of pituitary pars intermedia dysfunction (PPID) and was being treated with 250 μg (2.45 μg/kg PO) of pergolide (Bohringer Ingelheim, Ingelheim am Rhein, Germany) once daily. The mare also had a previous episode of mild laminitis.
On presentation, body condition score was 4/9 with the ribs slightly visible and decreased topline musculature. Digital pulses were within normal limits. A shortened stride in the hind limbs was evident at the walk, but no overt lameness was present. Palpation of the throatlatch region was unremarkable. A plasma biochemical analysis disclosed increased total calcium (17.79 mg/dL; RR, 10.7-13.4 mg/dL) and normal plasma phosphorus (3.01 mg/dL; RR, 1.9-5.4 mg/dL) concentrations. Radiographs of the metacarpi and metatarsi showed mild generalized osteopenia as evidenced by porosity, mostly affecting the proximal sesamoid bones.
On ultrasonography (Aplio i700, Canon Medical Systems USA, Inc, Tustin, CA), the right and left thyroid lobes were homogenous with normal echogenicity, architecture, and size ( Figure 1A,B). A discrete hypoechoic mass was present axial to the right thyroid lobe, measuring approximately 1 cm in diameter ( Figure 1C). A smaller (approximately 0.4 cm diameter) structure with similar echogenicity was present axial to the left thyroid lobe ( Figure 1D). These were suspected to represent parathyroid tissue, with that on the right side markedly increased in size compared to the left. No other masses or abnormalities were observed ultrasonographically.
Technetium ( 99m Tc) sestamibi scintigraphy was performed to confirm the enlarged parathyroid gland as the site of increased metabolic activity. It also was used to rule out additional sites of ectopic parathyroid tissue, because normal anatomical variation can include a pair of parathyroid glands in the region of the thyroid and an additional caudal pair of parathyroid glands that can vary in location from the bifurcation of the carotid trunk to the ventral aspect of the cranial third of the neck. 1

| DISCUSSION
We ablated the functional parathyroid tissue in the horse of this report using percutaneous ultrasound-guided ethanol injection, which resulted in rapid and sustained amelioration of hypercalcemia and increased serum PTH. We also used 3-phase contrast CT for detection of parathyroid tissue and procedural planning of parathyroid gland ablation. Although biopsy was not performed before ablation to confirm the nature of the mass, primary hyperparathyroidism due to parathyroid adenoma or hyperplasia was strongly suspected.
Primary hyperparathyroidism is considered uncommon in the horse, 5 and may be suspected with a combination of clinical signs such as weight loss, facial swelling, inappetence and shifting lameness. 6,7 It most often is caused by parathyroid hyperplasia or adenoma of the parathyroid gland and can result from single or multigland disease resulting in overproduction of endogenous PTH. 8,9 Parathyroid hormone is known to increase plasma calcium concentrations by increased intestinal absorption, decreased renal excretion and increased mobilization of calcium from bone. 2 In primary hyperparathyroidism, a lack of parathyroid gland response to negative feedback from increasing plasma concentrations of calcium or calcitriol as well as excessive synthesis of PTH are observed. 10 The hypercalcemia observed in this mare included both total and ionized calcium which, coupled with the increased serum PTH concentration, is highly suggestive of primary hyperparathyroidism.
Osteopenia of long bones can be seen with primary hyperparathyroidism as a result of mobilization of calcium from bone 6  However, nutritional secondary hyperparathyroidism presents with normocalcemia or hypocalcemia and concurrent hyperphosphatemia. 11 Additionally, our mare did not have a history of disproportionate calcium and phosphorous intake or ingestion of oxalates to support secondary hyperparathyroidism. 12 Cases of primary hyperparathyroidism in humans are most often caused by solitary parathyroid adenomas (80% of cases) or hyperplasia (10%-15% of cases) with the remainder of cases involving multiple gland adenomas or less commonly carcinomas. 13 In this mare, the to confirm the nodule as parathyroid tissue. In humans, sestamibi scintigraphy has a reported sensitivity of 65% and specificity of 88% for localization to side of the neck. 14 Limited information is available for horses, but 10/11 horses with suspected primary hyperparathyroidism were positive on sestamibi scintigraphy in 1 study. 15 The limitations for identification of parathyroid adenoma or hyperplasia in people include the size of the lesion relative to the spatial resolution of nuclear scintigraphy, with improved sensitivity for nodules >500 mg, relative insensitivity and decreased specificity in multigland disease, 16 and relative insensitivity for detection of hyperplasia compared to adenoma. 17 Negative sestamibi scans have accompanied confirmed cases of parathyroid adenomas in horses, 7 and although our patient had a positive scan, it did not rule out the potential for additional abnormal parathyroid tissue in the region of the proximal neck.
In addition to sestamibi and ultrasonographic imaging, contrastenhanced CT has been used in human medicine for both diagnosis and preoperative localization of parathyroid adenomas since 2006, with the advent of minimally invasive parathyroidectomy surgery. 14,18 This scanning method employs CT image acquisition with ≥2 contrast material-enhanced phases, resulting in 3-dimensional images, with the fourth dimension being time. The documented contrast enhancement pattern for parathyroid adenomas includes peak enhancement in the arterial phase and washout in the delayed (venous) phase. 3,14 Although ultrasound provides anatomic localization and sestamibi scintigraphy identifies additional aberrant foci, contrast CT shows excellent detail for preoperative and preprocedural localization, and the appearance of the lesion on different phases can help differentiate parathyroid adenomas and hyperplasia from surrounding lymph nodes or thyroid nodules. 3,14 Contrast CT as a second-line modality has a reported 70% to 92.5% sensitivity for the localization of parathyroid adenomas to a precise location in the neck with 33% to 46% sensitivity reported for sestamibi imaging and 29% to 38.5% for ultrasound in patients in some studies. 14,19,20 Additionally Achieving a decrease in circulating serum PTH concentration is imperative in the treatment of primary hyperparathyroidism in order to decrease progression of otseodystrophy and avoid complications such as pathologic fracture and organ calcification. Parathyroidectomy is considered the only curative procedure in humans and is recommended for symptomatic patients as well as individuals with subclinical end-organ sequelae. 13 Parathyroidectomy is described in the horse, with 1 case study involving removal of a mass at the thoracic inlet resulting in an immediate 95% decrease in serum PTH concentration. 5 Alternative procedures to parathyroidectomy include ultrasound-guided heat ablation 22,23 and alcohol ablation, 23 both of which have been successful in dogs. 21 The benefits of ablation include lower cost, decreased invasiveness and decreased anesthesia time compared to parathyroidectomy. 24 In dogs, medical management can be attempted including diuresis to decrease plasma calcium concentration. 25 In 1 report, all 7 horses that received medical treatment alone remained hypercalcemic. 15 Complications associated with parathyroidectomy are not well documented in horses, but can include acute kidney injury and hypocalcemic tetany. 5 In dogs, damage to the recurrent laryngeal nerves and major blood vessels has been documented 13 and in the mare of this report, close proximity of the mass to the jugular vein, carotid artery and recurrent laryngeal nerve increased the perceived risk of either parathyroidectomy or ablation. It is unclear whether or not ethanol ablation decreases the relative risk of these complications. Hypocalcemia is the most common complication of either treatment in dogs, occurring in approximately 40% of cases after either parathyroidectomy or ablation. 24,25 The additional risk of fracture inherently associated with general anesthesia also must be considered in horses, 26 and an advantage of ablation may be shortened anesthesia time. Prospective studies comparing parathyroidectomy with ablation across species are warranted. In this case, ablation was performed without apparent complication.
The increase in this mare's serum PTH concentration between 8 and 15 months after the procedure possibly was caused by the presence of additional active ectopic parathyroid tissue that was not identified with our imaging modalities, or incomplete success of the ablation procedure. Delayed recurrence of hypercalcemia after ablation has been documented in dogs. 23 Because the previously hyperactive gland was not readily identified and the total and ionized calcium concentrations were normal at follow-up, the mare was discharged with instructions to serially monitor serum PTH and calcium concentrations and these subsequently returned to normal at 30 months postablation without intervention.
In summary, we performed ethanol ablation of the parathyroid gland after localization of abnormal tissue using a combination of ultrasound, scintigraphy, and contrast CT. This procedure was successful with no observed adverse effects. A case series or prospective controlled study may provide confirmation of efficacy of percutaneous ultrasound-guided alcohol ablation for other equids with primary hyperparathyroidism as well as discrete mass identification.

ACKNOWLEDGMENT
No funding was received for this study.